Novel 1,2,4-thiadiazolium derivatives as melanocortin receptor modulators

ABSTRACT

The present invention is directed to novel 1,2,4-thiadiazol-2-ium derivatives useful as agonists or antagonists of the melanocortin receptor. More particularly, the compounds of the present invention are useful for the treatment of metabolic, CNS and dermatological disorders such as obesity, impaired oral glucose tolerance, elevated blood glucose levels, type II diabetes, Syndrome X, diabetic retinopathy, spinal cord injury, nerve injury, acute neurodegenerative disorders, chronic neurodegenerative disorders, plexopathies, male erectile dysfunction, dry eyes, acne, dry skin, aged skin, seborrheic dermatitis, rosacea, excessive ear wax, meibomian gland disorder, pseudofolliculitis, yeast infections, dandruff, hidradenitis suppurativa, ocular rosacea and eccrine gland disorder.

CROSS REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of U.S. ProvisionalApplication No. 60/337,762, filed on Nov. 8, 2001, which is incorporatedby reference herein in its entirety.

FIELD OF THE INVENTION

[0002] The present invention provides novel 1,2,4-thiadiazol-2-iumderivatives useful for the treatment of a disorder mediated by amelanocortin receptor. More particularly, the compounds of the presentinvention are useful for the treatment of metabolic, CNS anddermatologic disorders such as obesity, impaired oral glucose tolerance,elevated blood glucose levels, type II diabetes, Syndrome X, diabeticretinopathy, acute neurodegenerative disorders, chronicneurodegenerative disorders, plexopathies, male erectile dysfunction,dry eyes, acne, dry skin, aged skin, seborrheic dermatitis, rosacea,excessive ear wax, meibomian gland disorder, pseudofolliculitis, yeastinfections, dandruff, hiradenitis suppurativa, ocular rosacea andeccrine gland disorder.

BACKGROUND OF THE INVENTION

[0003] Melanocortins are neuropeptides that arise frompro-opiomelanocortin (POMC), which is most prevalently expressed in thearcuate nucleus of the hypothalamus, pituitary lobes, and the nucleustractus solarius of the brainstem. [Gantz, I., et al., MolecularCloning, Expression, and Gene Localization of a Fourth MelanocortinReceptor, J. Biolog. Chem., 1993, 268, 15174-15179.] These peptidesinclude ACTH, α-MSH, β-MSH, γ₁₋₃-MSH, and synthetic analogue NDP-αMSH(Wikberg, J E S, Melanocortin receptors: new opportunities in drugdiscovery, Exp. Opin. Ther. Patents, 2000, 11(1), 61-76).

[0004] These peptides bind to five types of melanocortin receptors(MC1-MC5), which are G-protein coupled receptors that all positivelymodulate adenylate cyclase. The MC4 and MC5 receptors are widelydistributed in the brain and spinal cord, whereas the MC3 receptor islocated mainly in the hypothalamus. [Gantz, I., et al., supra.] The MC4receptor is selectively activated by αMSH and can induce neuriteoutgrowth in Neuro 2A cells. (Adan R. A. H, et al., Molecular BrianResearch, 1996, 36, pp 37-44; Mountjoy, K. G., Mortud, M. T., Low, M.J., Simerly, R. B. and Cone, R. D., Mol. Endocrinol., 1994, 8, pp1298-1308). ACHT is a less potent activator of the MC4 receptor thanαMSH. (Adan, R. A. H., Cone, R. D., Burbach, J. P. H. and Gispen, W. H.,mol. pharmacol., 1994, 46, pp 1182-1190). The MC5 receptor is activated,in order of degree, by NDP≈α-MSH>ACHT (1-24)≧α MSH ACHT (1-39)=βMSH>>γMSH (The Melanocortin Receptors, Cone, R. D., Editor, Human PressInc., Totowa, N.J., 2000, Chen, W., pp449-472)

[0005] In whole animals, studies in the rat sciatic nerve crush modelhave demonstrated that α-MSH increases neurite outgrowth and, as themost potent of the ACTH derived peptides, it significantly promotesnerve terminal branching, endplate area, and perimeter. [Bijlsma, W. A.,et al., The Enhanced Recovery of Sensorimotor Function in Rats isRelated to the Melantropic Moiety of ACTH/MSH Neuropeptides, Eur. J.Pharmacol, 1983, 92, 231-236; Van der Neut. R., et al., Stimulation byMelanocortins of Neurite Outgrowth from Spinal and Sensory Neurons InVitro, Peptides, 1992, 13, 1109-1115; Van Der Zee, C. E. E. M., et al.,α-MSH and Org 2766 in Peripheral Nerve Regeneration: Different Route ofDelivery, Eur. J. Pharmacol., 1988, 147, 351-357; Strand, F. L., et al.,Melanocortins as Factors in Somatic Neuromuscular Growth and Regrowth,Pharmac. Ther., 1994, 62, 1-27]. Furthermore, recovery of motor functionafter nerve injury is shortened by application of α-MSH and othermelanocortins. [Strand, F. L., et al., supra]

[0006] Mice in which the MC4 receptor is rendered inactive by genetargeting become obese, suggesting that the MC4 receptor is involved infeeding. [Huszar, D., et al., Targeted Disruption of the Melanocortin-4Receptor Results in Mice, Cell, 1997, 88, 131-141] This is substantiatedby a report that various MC4 peptide agonists inhibit feeding behaviorin agouti mice. [Fan, W., et al., Role of Melanocortingenic Neurons inFeeding and the Agouti Obesity Syndrome, Nature, 1997, 385, 165-168].α-MSH induces grooming behavior in rats, but the significance of this isnot clear and may not be mediated via the MC4 receptor. [Adan, R. A. H.,et al., Differential Effects of Melanocortin Peptides on NeuralMelanocortin Receptors, Molecular Pharmacology, 1994, 46, 1182-1190].

[0007] The melanocortins αMSH and ACTH are also known for their abilityto stimulate pigmentation and adrenal glucocorticoid secretion,respectively. The role of melanocortins, particularly αMSH, in theregulation of sebaceous gland activity (an exocrine gland with holocrinetype of secretion) was shown originally in rats. More particularly, thestudies showed that removal of the intermediate lobe of the pituitary(which produces the POMC peptides) resulted in decreased sebaceous lipidproduction, with complete restoration to normal levels after replacementtherapy with αMSH (Thody, A. J. and Shuster, Nature, 237, 346-347,1972). In a study of rats following total hypophysectomy, treatment withαMSH resulted in an increase of sebum production, although fullrestoration of sebum production was achieved only after treatment with acombination of αMSH and testosterone (Thody, A. J., Shuster, S., J.Endocr. 64, 503-510, 1975; Ebling, F. J., Ebling, E., Randall, V. andSkinner, J., J. Endocr. 66, 407-412, 1975). Knock-out mice where the MC5receptor was deleted were observed to display a severe defect in waterrepulsion and thermo-regulation, due to decreased production ofsebaceous lipids (Chen, W. Kelly, M. A., Opitz-Araya, X., Thomas, R. E.,Low, M. J., and Cone, R., Cell, 91, 788-798, 1997).

[0008] The MC5 receptor is known to be expressed in human sebaceousglands, and may be involved in the regulation of human sebaceous lipidsynthesis. Human MC5-R has been cloned and characterized (Chhajlani, V.,Muceniece, R., Wikberg, J E S., Biochem. Biophys. Res. Commun. 195,866-873, 1993). Moreover, presence of MC5-R m RNA in human sebaceousglands has been shown by RT-PCR and the protein was detected byimmunohistochemistry and Western blot analysis (Thiboutot, D.,Sivarajah, Gililand, K., Cong, Z. and Clawson, G., J. Invest. Dermatol.115(4), 614-619, 2000).

[0009] Human sebum differs in its composition from other mammals. Themain lipids in human sebum are triglycerides, wax esters and squalene(Greene, R. S., Downing, D. T., Poci, P. E., Strauss, J. S., JID 54,240-247, 1970). Squalene, for instance is not found in many mammals withthe exception of otter and beaver. Triglyceride, which is a majorcomponent of human sebum is poorly represented in other species and inmany (e.g. chimpanzee) appears to be totally absent (Thody, A. J.,Shuster, S., Physiolog. Rev. 69, 383-415, 1989). Moreover melanocortinscan have different effects on cells from different species. For exampleboth αMSH (EC₅₀=3.7 nM) and ACTH (EC₅₀=16.4 nM) are potent lipolyticagents for rabbit adipocytes, whereas in the rat only ACTH (EC₅₀=1.34nM) has potent lipolytic activity (Ramachadran, J., Lee, V., 428,339-346, 1987; Richter, W. O., Schwandt, P., Neuropeptides 9, 59-74,1987). Despite lipolytic activity in rodents and rabbits, ACTH has verylittle effect on lipolysis in isolated human and non-human primateadipocytes, even at concentrations as high as 1 μM (Ng, T. B.Comparative Biochem. 97, 441-446, 1990). Thus defining the role ofmelanocortins and their receptors in animal sebaceous model systems isnot necessarily predictive of their role in a human sebaceous lipidregulation.

[0010] Recently, Basu et. al., in WIPO publication WO99/55679 disclosedisoquinoline derivatives, small molecule non-peptide compounds, whichshowed low micromolar affinities for the MC1 and MC4 receptors,reduction of dermal inflammation induced by arachidonic acids, andreductions of body weight and food intake.

[0011] Nargund et. al., in WIPO publication WO99/64002 disclosedspiropiperidine derivatives as melanocortin receptor agonists, usefulfor the treatment of diseases and disorders such as obesity, diabetesand sexual dysfunction.

[0012] Thus there exist a need for small molecule modulators of themelanocortin receptor, more particularly the melanocortin-3,melanocortin-4 and/or the melanocortin-5 receptors.

SUMMARY OF THE INVENTION

[0013] The present invention is directed to compounds of the generalformula (I)

[0014] wherein

[0015] R¹ is selected from the group consisting of aryl, aralkyl,heteroaryl, heteroaryl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl,cycloalkyl and cycloalkyl-alkyl; wherein the aryl, aralkyl, heteroaryl,heterocycloalkyl, heterocycloalkyl-alkyl or cycloalkyl group isoptionally substituted with one or more substituents independentlyselected from halogen, hydroxy, alkyl, alkoxy; halogenated alkyl,halogenated alkoxy, amino, alkylamino or di(alkyl)amino;

[0016] R² is selected from the group consisting of aryl, aralkyl,heteroaryl, heterocycloalkyl and cycloalkyl-alkyl; wherein the aryl,aralkyl, heteroaryl, heterocycloalkyl or cycloalkyl group is optionallysubstituted with one or more substituents independently selected fromhalogen, hydroxy, alkyl, alkoxy; halogenated alkyl, halogenated alkoxy,amino, alkylamino or di(alkyl)amino;

[0017] R³ is selected from the group consisting of hydrogen, alkyl,alkenyl and alkynyl; wherein the double bond of the alkenyl or thetriple bond of the alkynyl group is at least one carbon atom removedfrom the point of attachment;

[0018] R⁴ is selected from the group consisting of aryl, aralkyl,heteroaryl, heterocycloalkyl, and cycloalkyl-alkyl; wherein the aryl,aralkyl, heteroaryl, heterocycloalkyl or cycloalkyl group is optionallysubstituted with one or more substituents independently selected fromhalogen, hydroxy, alkyl, alkoxy; halogenated alkyl, halogenated alkoxy,amino, alkylamino or di(alkyl)amino;

[0019] X⁻ is selected from the group consisting of bromide, chloride,iodide, acetate, benzoate, citrate, lactate, malate, nitrate, phosphate,diphosphate, succinate, sulfate, tartrate and tosylate;

[0020] provided that when R¹ is phenyl, chlorophenyl or benzyl, R² isphenyl or benzothienyl and R⁴ is phenyl or aralkyl, then R³ is selectedfrom the group consisting of alkyl, alkenyl and alkynyl; wherein thedouble bond of the alkenyl or the triple bond of the alkynyl group is atleast one carbon atom removed from the point of attachment;

[0021] provided further that when R¹ is benzyl or methylphenyl, R² isphenyl or methylphenyl and R⁴ is methylphenyl or 4-methoxyphenyl, thenR³ is selected from the group consisting of alkyl, alkenyl and alkynyl;wherein the double bond of the alkenyl or the triple bond of the alkynylgroup is at least one carbon atom removed from the point of attachment;

[0022] provided further that when R¹ is phenyl, R² is phenyl and R⁴ isphenyl, then R³ is selected from the group consisting of C₃₋₈alkyl (i.e.not methyl or ethyl), alkenyl and alkynyl; preferably, R³ is selectedfrom the group consisting of alkenyl and alkynyl; wherein the doublebond of the alkenyl or the triple bond of the alkynyl group is at leastone carbon atom removed from the point of attachment;

[0023] and pharmaceutically acceptable salts thereof.

[0024] The present invention is further directed to a method of treatinga disorder mediated by a melanocortin receptor comprising administeringto a subject in need thereof a therapeutically effective amount of acompound of formula (I)

[0025] R¹ is selected from the group consisting of alkyl, aryl, aralkyl,heteroaryl, heteroaryl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl,cycloalkyl and cycloalkyl-alkyl; wherein the aryl, aralkyl, heteroaryl,heteroaryl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, cycloalkylor cycloalkyl-alkyl group is optionally substituted with one or moresubstituents independently selected from halogen, hydroxy, alkyl,alkoxy; halogenated alkyl, halogenated alkoxy, amino, alkylamino ordi(alkyl)amino;

[0026] R² is selected from the group consisting of alkyl, aryl, aralkyl,heteroaryl, heterocycloalkyl and cycloalkyl-alkyl; wherein the aryl,aralkyl, heteroaryl, heterocycloalkyl or cycloalkyl-alkyl group isoptionally substituted with one or more substituents independentlyselected from halogen, hydroxy, alkyl, alkoxy; halogenated alkyl,halogenated alkoxy, amino, alkylamino or di(alkyl)amino;

[0027] R³ is selected from the group consisting of hydrogen, alkyl,alkenyl and alkynyl; wherein the double bond of the alkenyl or thetriple bond of the alkynyl group is at least one carbon atom removedfrom the point of attachment;

[0028] R⁴ is selected from the group consisting of hydrogen, alkyl,aryl, aralkyl, heteroaryl, heterocycloalkyl, and cycloalkyl-alkyl;wherein the aryl, aralkyl, heteroaryl, heterocycloalkyl orcycloalkyl-alkyl group is optionally substituted with one or moresubstituents independently selected from halogen, hydroxy, alkyl,alkoxy; halogenated alkyl, halogenated alkoxy, amino, alkylamino ordi(alkyl)amino;

[0029] X⁻ is selected from the group consisting of bromide, chloride,iodide, acetate, benzoate, citrate, lactate, malate, nitrate, phosphate,diphosphate, succinate, sulfate, tartrate and tosylate;

[0030] and pharmaceutically acceptable salts thereof.

[0031] Illustrative of the invention is a pharmaceutical compositioncomprising a pharmaceutically acceptable carrier and any of thecompounds described above. An illustration of the invention is apharmaceutical composition made by mixing any of the compounds describedabove and a pharmaceutically acceptable carrier. Illustrating theinvention is a process for making a pharmaceutical compositioncomprising mixing any of the compounds described above and apharmaceutically acceptable carrier.

[0032] Exemplifying the invention are methods of treating disordersmediated by the melanocortin receptor in a subject in need thereofcomprising administering to the subject a therapeutically effectiveamount of any of the compounds or pharmaceutical compositions describedabove.

[0033] An embodiment of the present invention is the use of any of thecompounds described herein for the treatment of a disorder selected fromthe group consisting of metabolic disorders, CNS disorders anddermatological disorders.

[0034] An example of the invention is a method for treating a disorderselected from the group consisting of obesity, impaired oral glucosetolerance, elevated blood glucose levels, type II diabetes, Syndrome X,diabetic retinopathy, spinal cord injury, nerve injury, acuteneurodegenerative disorders, chronic neurodegenerative disorders,plexopathies, male erectile dysfunction, dry eyes, acne, dry skin, agedskin, seborrheic dermatitis, rosacea, excessive ear wax, meibomian glanddisorder, pseudofolliculitis, yeast infections, dandruff, hidradenitissuppurativa, ocular rosacea and eccrine gland disorder in a subject inneed thereof comprising administering to the subject a therapeuticallyeffective amount of any of the compounds or pharmaceutical compositionsdescribed above.

[0035] Another example of the invention is the use of any of thecompounds described herein in the preparation of a medicament fortreating: (a) obesity, (b) impaired oral glucose tolerance, (c) elevatedblood glucose levels, (d) type II diabetes, (e) Syndrome X, (f) diabeticretinopathy, (g) an acute neurodegenerative disorder, (h) a chronicneurodegenerative disorder, (i) a plexopathy, (j) male erectiledysfunction, (k) dry eyes, (l) acne, (m) dry skin, (n) aged skin, (o)seborrheic dermatitis, (p) rosacea, (q) excessive ear wax, (r) meibomiangland disorder, (s) pseudofolliculitis, (t) yeast infections, (u)dandruff, (v) hidradenitis suppurativa, (w) ocular rosacea or (x)eccrine gland disorder, in a subject in need thereof.

DETAILED DESCRIPTION OF THE INVENTION

[0036] The present invention is directed to novel substituted1,2,4-thiadiazol-2-ium derivatives useful for the treatment of disordersmediated by a melanocortin receptor. More particularly, the presentinvention is directed to compounds of formula (I)

[0037] wherein X, R¹, R², R³ and R⁴ are as herein defined, useful asmelanocortin receptor agonists or antagonists.

[0038] The present invention is further directed to a method of treatinga disorder mediated by a melanocortin receptor, preferably a disorderwhich is susceptible to treatment by agonism or antagonism of amelanocortin receptor. Preferably the melanocortin receptor is selectedfrom the group consisting of the melanocortin-3, melanocortin-4 andmelanocortin-5 receptor, more preferably the melanocortin receptor ismelanocortin-4 or melanocortin-5.

[0039] Preferably, R¹ is selected from the group consisting of aryl,aralkyl and heteroaryl; wherein the aryl, aralkyl or heteroaryl group isoptionally substituted with one or more substituents independentlyselected from halogen, hydroxy, alkyl, alkoxy, trihalomethyl,trihalomethoxy, amino, alkylamino or di(alkyl)amino. More preferably, R¹is selected from the group consisting of aryl; wherein aryl group isoptionally substituted with one or more substituents independentlyselected from halogen, alkyl and alkoxy. More preferably still, R¹ isselected from the group consisting of phenyl, 2-chlorophenyl,4-chlorophenyl, 2-methylphenyl, 4-methylphenyl, 2-methoxyphenyl and4-methoxyphenyl. Most preferably R¹ is 2-methoxyphenyl.

[0040] Preferably, R² is selected from the group consisting of aryl,aralkyl and heteroaryl; wherein the aryl, aralkyl or heteroaryl group isoptionally substituted with one or more substituents independentlyselected from halogen, hydroxy, alkyl, alkoxy, trihalomethyl,trihalomethoxy, amino, alkylamino or di(alkyl)amino. More preferably, R²is selected from the group consisting of aryl; wherein the aryl group isoptionally substituted with one or more substituents independentlyselected from alkyl and alkoxy. More preferably still, R² is selectedfrom the group consisting of phenyl, 4-methylphenyl, 2-methoxyphenyl and4-methoxyphenyl. Most preferably, R² is selected from the groupconsisting of phenyl and 2-methoxyphenyl.

[0041] Preferably, R³ is selected from the group consisting of hydrogenand alkyl. More preferably, R³ is selected from the group consisting ofhydrogen and methyl.

[0042] Preferably, R⁴ is selected from the group consisting of aryl,aralkyl and heteroaryl; wherein the aryl, aralkyl or heteroaryl group isoptionally substituted with one or more substituents independentlyselected from halogen, hydroxy, alkyl, alkoxy, trihalomethyl,trihalomethoxy, amino, alkylamino or di(alkyl)amino. More preferably, R⁴is selected from the group consisting of aryl, aralkyl, and heteroaryl;wherein the aryl or aralkyl group is optionally substituted with one ormore substituents independently selected from halogen, alkyl and alkoxy.More preferably still, R⁴ is selected from the group consisting ofphenyl, 2-chlorophenyl, 4-chlorophenyl, 4-bromophenyl, 2-methylphenyl,4-methylphenyl, 2-methoxyphenyl, 4-methoxyphenyl, benzyl,2-chlorobenzyl, 4-chlorobenzyl, 2-methylbenzyl, 4-methylbenzyl,2-methoxybenzyl, 4-methoxybenzyl, 2,6-difluorophenyl,3,5-difluorophenyl, 2-chloro-6-methylphenyl and 3-pridyl. Mostpreferably, R⁴ is selected from the group consisting of phenyl,2-methylphenyl, 4-methylphenyl, 2-methoxyphenyl and 4-methoxyphenyl.

[0043] In a class of the invention are compounds of the formula (I)wherein R¹, R² and R⁴ are each independently selected from aryl andsubstituted aryl; and R³ is hydrogen.

[0044] Preferably X⁻ is selected from the group consisting of bromide,chloride, iodide, acetate, benzoate, citrate, lactate, malate, nitrate,phosphate, diphosphate, succinate, sulfate, tartrate and tosylate. Morepreferably, X⁻ is selected from the group consisting of bromide,chloride and iodide. Most preferably, X⁻ is bromide.

[0045] As used herein, unless otherwise noted, the term “disordersmediated by a melanocortin receptor” include, but are not limited to,obesity, impaired oral glucose tolerance, elevated blood glucose levels,type II diabetes, Syndrome X, diabetic retinopathy, acuteneurodegenerative disorders, chronic neurodegenerative disorders,plexopathies, male erectile dysfunction, dry eyes, acne, dry skin, agedskin, seborrheic dermatitis, rosacea, excessive ear wax, meibomian glanddisorder, pseudofolliculitis, yeast infections, dandruff, hidradenitissuppurativa, ocular rosacea and eccrine gland disorder.

[0046] As used herein, unless otherwise noted, the term “metabolicdisorders” include, but are not limited to, obesity, impaired oralglucose tolerance, elevated blood glucose levels, type II diabetes andSyndrome X.

[0047] As used herein, unless otherwise noted, the term “CNS disorder”includes, but is not limited to, diabetic retinopathy, acuteneurodegenerative disorders, chronic neurodegenerative disorders andplexopathies.

[0048] As used herein, unless otherwise noted, the term “dermatologicaldisorders” include, but are not limited to, dry eyes, acne, dry skin,aged skin, seborrheic dermatitis, rosacea, excessive ear wax, meibomiangland disorder, pseudofolliculitis, yeast infections, dandruff,hidradenitis suppurativa, ocular rosacea and eccrine gland disorder.

[0049] As used herein, acute neurodegenerative disorders include varioustypes of acute neurodegenerative disorders associated with neuronal celldeath or compromise including cerebrovascular insufficiency, focal ordiffuse brain trauma, diffuse brain damage, and spinal cord injury, thatis, cerebral ischemia or infarction including embolic occlusion andthrombotic occlusion, reperfusion following acute ischemia, perinatalhypoxic-ischemic injury, cardiac arrest, as well as intracranialhemorrhage of any type (including, but not limited to, epidural,subdural, subarachnoid and intracerebral), and intracranial andintravertebral lesions (including, but not limited to, contusion,penetration, shear, compression and laceration), and whiplash shakeninfant syndrome.

[0050] As used herein, chronic neurodegenerative disorders includedwithin the methods of the present invention include Alzheimer's disease,Pick's disease, diffuse Lewy body disease, progressive supranuclearpalsy (Steel-Richardson syndrome), multisystem degeneration (Shy-Dragersyndrome), chronic epileptic conditions associated withneurodegeneration, motor neuron diseases including amyotrophic lateralsclerosis, degenerative ataxias, cortical basal degeneration,ALS-Parkinson's-Dementia complex of Guam, subacute sclerosingpanencephalitis, Huntington's disease, Parkinson's disease,synucleinopathies (including multiple system atrophy), primaryprogressive aphasia, striatonigral degeneration, Machado-Josephdisease/spinocerebellar ataxia type 3 and olivopontocerebellardegenerations, Gilles De La Tourette's disease, bulbar and pseudobulbarpalsy, spinal and spinobulbar muscular atrophy (Kennedy's disease),primary lateral sclerosis, familial spastic paraplegia, Werdnig-Hoffmanndisease, Kugelberg-Welander disease, Tay-Sach's disease, Sandhoffdisease, familial spastic disease, Wohlfart-Kugelberg-Welander disease,spastic paraparesis, progressive multifocal leukoencephalopathy,familial dysautonomia (Riley-Day syndrome), and prion diseases(including, but not limited to Creutzfeldt-Jakob,Gerstmann-Sträussler-Scheinker disease, Kuru and fatal familialinsomnia).

[0051] As used herein, plexopathies include plexus palsies, multifocalneuropathies, sensory neuropathies, motor neuropathies, sensory-motorneuropathies, infections neuropathies, autonomic neuropathies,sensory-autonomic neuropathies, demyelinating neuropathies (including,but not limited to Guillain-Barre syndrome and chronic inflammatorydemyelinating polyradiculoneuropathy), other inflammatory and immuneneuropathies, neuropathies induced by drugs, neuropathies induced bypharmacological treatments, neuropathies induced by toxins, traumaticneuropathies (including, but not limited to compression, crush,laceration and segmentation neuropathies), metabolic neuropathies,endocrine and paraneoplastic neuropathies, and other neuropathies suchas Charcot-Marie-Tooth disease (type 1a, 1b, 2, 4a,1-X linked),Friedreich's ataxia, metachromatic leukodystrophy, Refsum's disease,adrenomyeloneuropathy, Ataxia-telangiectasia, Déjerine-Sottas neuropathy(types A and B), Lambert-Eaton syndrome, and disorders of the cranialnerves.

[0052] As used herein, unless otherwise noted, the term “halogen” shallinclude iodine, bromine, chlorine and fluorine.

[0053] As used herein, the term “alkyl” whether used alone or as part ofa substituent group, includes straight and branched chains comprisingone to eight carbon atoms. For example, alkyl radicals include methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyland the like. Unless otherwise noted, “lower” when used with alkyl meansa carbon chain composition of one to four carbon atoms.

[0054] The term “alkenyl”, whether used alone or as part of asubstituent group, shall include straight and branched alkene chainscomprising two to eight carbon atoms. Suitable examples include vinyl,1-propenyl, 2-propenyl, 1-butenyl. 2-butenyl, 1-pentenyl, 2-pentenyl,1-isobut-2-enyl, and the like. Similarly, the term “alkynyl”, whetherused alone or as part of a substituent group, shall include straight andbranched alkyne chains comprising two to eight carbon atoms. Suitableexamples include 2-propynyl, 2-butynyl, 1-butynyl, 1-pentynyl, and thelike.

[0055] As used herein, unless otherwise noted, “alkoxy” shall denote anoxygen ether radical of the above described straight or branched chainalkyl groups. For example, methoxy, ethoxy, n-propoxy, sec-butoxy,t-butoxy, n-hexyloxy and the like.

[0056] As used herein, unless otherwise noted, the term “cycloalkyl”shall denote saturated monocyclic ring structures comprising three toeight ring carbons, preferably 5 to 7 carbons. Suitable examples includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl andcyclooctyl.

[0057] As used herein, the term “aryl” indicates aromatic carbocyclicring structures such as phenyl, naphthyl, and the like.

[0058] As used herein, unless otherwise noted, “aralkyl” shall mean anylower alkyl group substituted with an aryl group. For example, benzyl,phenylethyl, phenylpropyl, naphthylmethyl, and the like.

[0059] As used herein, unless otherwise noted, “heteroaryl” shall denoteany five or six membered monocyclic aromatic ring structure containingat least one heteroatom selected from the group consisting of O, N andS, optionally containing one to three additional heteroatomsindependently selected from the group consisting of O, N and S; or anine or ten membered bicyclic aromatic ring structure containing atleast one heteroatom selected from the group consisting of O, N and S,optionally containing one to four additional heteroatoms independentlyselected from the group consisting of O, N and S. The heteroaryl groupmay be attached at any carbon atom of the ring such that the result is astable structure.

[0060] Examples of suitable heteroaryl groups include, but are notlimited to, pyrrolyl, furyl, thienyl, oxazolyl, imidazolyl, purazolyl,isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl, pyranyl, furazanyl, indolizinyl, indolyl,isoindolinyl, indazolyl, isoxazolyl, benzofuryl, benzothienyl,benzimidazolyl, benzthiazolyl, purinyl, quinolizinyl, quinolinyl,isoquinolinyl, isothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl,quinoxalinyl, naphthyridinyl, pteridinyl, and the like. Preferredheteroaryl groups include pyridyl, thienyl and imidazolyl.

[0061] As used herein, the term “heterocycloalkyl” shall denote any fiveto seven membered monocyclic, saturated, partially unsaturated orpartially aromatic ring structure containing at least one heteroatomselected from the group consisting of O, N and S, optionally containingone to three additional heteroatoms independently selected from thegroup consisting of O, N and S; or a nine to ten membered saturated,partially unsaturated or partially aromatic bicyclic ring systemcontaining at least one heteroatom selected from the group consisting ofO, N and S, optionally containing one to four additional heteroatomsindependently selected from the group consisting of O, N and S. Theheterocycloalkyl group may be attached at any carbon atom of the ringsuch that the result is a stable structure.

[0062] Examples of suitable heterocycloalkyl groups include, but are notlimited to, pyrrolinyl, pyrrolidinyl, dioxalanyl, imidazolinyl,imidazolidinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, dioxanyl,morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl,indolinyl, chromenyl, 3,4-methylenedioxyphenyl, 2,3-dihydrobenzofuryl,and the like.

[0063] As used herein, the notation “*” shall denote the presence of astereogenic center.

[0064] Where the compounds according to this invention have at least onechiral center, they may accordingly exist as enantiomers. Where thecompounds possess two or more chiral centers, they may additionallyexist as diastereomers. It is to be understood that all such isomers andmixtures thereof are encompassed within the scope of the presentinvention. Furthermore, some of the crystalline forms for the compoundsmay exist as polymorphs and as such are intended to be included in thepresent invention. In addition, some of the compounds may form solvateswith water (i.e., hydrates) or common organic solvents, and suchsolvates are also intended to be encompassed within the scope of thisinvention.

[0065] When a particular group is “substituted” (e.g., cycloalkyl, aryl,aralkyl, heteroaryl, heterocycloalkyl), that group may have one or moresubstituents, preferably from one to five substituents, more preferablyfrom one to three substituents, most preferably from one to twosubstituents, independently selected from the list of substituents.

[0066] It is intended that the definition of any substituent or variableat a particular location in a molecule be independent of its definitionselsewhere in that molecule. It is understood that substituents andsubstitution patterns on the compounds of this invention can be selectedby one of ordinary skill in the art to provide compounds that arechemically stable and that can be readily synthesized by techniques knowin the art as well as those methods set forth herein.

[0067] Under standard nomenclature used throughout this disclosure, theterminal portion of the designated side chain is described first,followed by the adjacent functionality toward the point of attachment.Thus, for example, a “phenylC₁-C₆alkylaminocarbonylC₁-C₆alkyl”substituent refers to a group of the formula

[0068] The term “subject” as used herein, refers to an animal,preferably a mammal, most preferably a human, who is or has been theobject of treatment, observation or experiment.

[0069] As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombinations of the specified ingredients in the specified amounts.

[0070] The term “therapeutically effective amount” as used herein, meansthat amount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue system, animal or humanthat is being sought by a researcher, veterinarian, medical doctor orother clinician, which includes alleviation of the symptoms of thedisease or disorder being treated.

[0071] For use in medicine, the salts of the compounds of this inventionrefer to non-toxic “pharmaceutically acceptable salts”. Other salts may,however, be useful in the preparation of compounds according to thisinvention or of their pharmaceutically acceptable salts. Suitablepharmaceutically acceptable salts of the compounds of this inventioninclude acid addition salts which may, for example, be formed by mixinga solution of the compound with a solution of a pharmaceuticallyacceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid,maleic acid, succinic acid, acetic acid, benzoic acid, citric acid,tartaric acid, carbonic acid or phosphoric acid.

[0072] The present invention includes within its scope prodrugs of thecompounds of this invention. In general, such prodrugs will befunctional derivatives of the compounds which are readily convertible invivo into the required compound. Thus, in the methods of treatment ofthe present invention, the term “administering” shall encompass thetreatment of the various disorders described with the compoundspecifically disclosed or with a compound which may not be specificallydisclosed, but which converts to the specified compound in vivo afteradministration to the patient. Conventional procedures for the selectionand preparation of suitable prodrug derivatives are described, forexample, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

[0073] Abbreviations used in the instant specification, particularly theSchemes and Examples, are as follows: BHT =2,6-bis-(t-butyl)-4-methyl-phenol BSA = Bovine Serum Albumin cAMP or =Cyclic-adenosine monophosphate cyclic AMP DCE = 1,2-dichloroethane DEAD= Diethyl azodicarboxylate DM = Differentiation Medium DMF = Dimethylformamide DMEM = Dulbeccos Minimal Essential Medium DMSODimethylsulfoxide DPBS = Dulbeccos phosphate buffered saline EDTA =Ethylene Diamine Tetraacetic Acid FBS = Fetal bovine serum GDP =Guanosine Diphosphate GTP = Guanosine Triphosphate GM = Growth MediumHBSS = Hank's Buffered salt Solution HEPES =4-(2-Hydroxyethyl)-1-pipenzine ethane sulfonic acid HS = Human Serum IgG= Immunoglobulin G % Inh = Percent Inhibition MEM = Minimum EssentialMedium NBS = N-bromosuccinimide NCS = N-chlorosuccinimide NDP αMSH =[Nle⁴, D-Phe⁷]αMSH, an analog of αMSH PBS = Phosphate Buffered salinePEG = Polyethylene Glycol PNC = Penicillin rt or RT = Room TemperatureSPA = Scintillation Proximity Assay STM = Streptomycin TLC = Thin layerchromatography TM = Transition Medium TMS = Trimethylsilyl

[0074] Compounds of formula (I) wherein R³ is hydrogen may be preparedaccording to the process outlined in Scheme 1.

[0075] More particularly, a suitably substituted cyano compound offormula (III), a known compound or compound prepared by known methods,is reacted with a suitably substituted primary amine of formula (IV), aknown compound or compound prepared by known methods, in the presence ofa base such as NaNH₂, NaH, NaN(TMS)₂, and the like, preferably NaNH₂, atan elevated temperature, preferably at about reflux, to yield thecorresponding compound of formula (V).

[0076] The compound of formula (V) is reacted with a suitablysubstituted thiocyanate of formula (VI), a known compound or compoundprepared by known methods, in the presence of DCE, at an elevatedtemperature, preferably about 45° C., to yield the correspondingcompound of formula (VII).

[0077] The compound of formula (VII) is subjected to ringclosure/oxidation, in the presence of Br₂, at room temperature, to yieldthe corresponding compound of formula (Ia).

[0078] Compounds of formula (II) may be prepared from suitablysubstituted compounds of formula (I) wherein R³ is hydrogen according tothe process outlined in Scheme 2.

[0079] More particularly, a suitably substituted compound of formula(Ia) is treated with a base such as NaHCO₃, Na₂CO₃, NaOH, and the like,preferably NaHCO₃, at room temperature, to yield the correspondingcompound of formula (II).

[0080] Compounds of formula (II) may also be prepared from suitablysubstituted compounds of formula (VII) according to the process outlinedin Scheme 3.

[0081] More particularly, a suitably substituted compound of formula(VII) is reacted with an oxidizing agent such as NBS, NCS, DEAD, and thelike, preferably NBS, at room temperature, to yield the correspondingcompound of formula (II). Preferably, the compound of formula (II) isextracted from a basic aqueous solution such as NaHCO₃, Na₂CO₃, NaOH,and the like.

[0082] Compounds of formula (I) wherein R³ is alkyl may be prepared froma suitably substituted compound of formula (II) according to the processoutlined in Scheme 4.

[0083] Accordingly, a suitably substituted compound of formula (II) isreacted with a suitably substituted compound of formula (VIII), a knowncompound or compound prepared by known methods, wherein X⁻ istrifluoromethylsulfonate, Br⁻ or I⁻, at room temperature, to yield thecorresponding compound of formula (I).

[0084] Compounds of formula (I) wherein R³ is hydrogen may be preparedfrom a suitably substituted compound of formula (II) according to theprocess outlined in Scheme 5.

[0085] Accordingly, a suitably substituted compound of formula (II) isreacted with a pharmaceutically acceptable acid such as HCl, HBr, HNO₃,and the like, preferably HCl, at room temperature, to yield thecorresponding compound of formula (Ia), wherein X⁻ is Cl⁻, Br⁻, NO₃ ⁻,and the like.

[0086] Where the processes for the preparation of the compoundsaccording to the invention give rise to mixture of stereoisomers, theseisomers may be separated by conventional techniques such as preparativechromatography. The compounds may be prepared in racemic form, orindividual enantiomers may be prepared either by enantiospecificsynthesis or by resolution. The compounds may, for example, be resolvedinto their components enantiomers by standard techniques, such as theformation of diastereomeric pairs by salt formation with an opticallyactive acid, such as (−)-di-p-toluoyl-d-tartaric acid and/or(+)-di-p-toluoyl-l-tartaric acid followed by fractional crystallizationand regeneration of the free base. The compounds may also be resolved byformation of diastereomeric esters or amides, followed bychromatographic separation and removal of the chiral auxiliary.Alternatively, the compounds may be resolved using a chiral HPLC column.

[0087] During any of the processes for preparation of the compounds ofthe present invention, it may be necessary and/or desirable to protectsensitive or reactive groups on any of the molecules concerned. This maybe achieved by means of conventional protecting groups, such as thosedescribed in Protective Groups in Organic Chemistry, ed. J. F. W.McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, John Wliey & Sons, 1991. The protectinggroups may be removed at a convenient subsequent stage using methodsknown from the art.

[0088] The utility of the compounds of the present invention to treatdisorders mediated by a melanocortin receptor can be determinedaccording to the procedures described in Examples 4-11 herein. Thepresent invention therefore provides a method of treating suchdisorders, which comprises administering any of the compounds as definedherein in a quantity effective to treat the disorder (i.e. in atherapeutically effective amount). The compound may be administered to apatient afflicted with such a disorder by any conventional route ofadministration, including, but not limited to, intravenous, oral,subcutaneous, intramuscular, intradermal, parenteral and transdermal.

[0089] The present invention also provides pharmaceutical compositionscomprising one or more compounds of this invention in association with apharmaceutically acceptable carrier.

[0090] To prepare the pharmaceutical compositions of this invention, oneor more compounds of formula (I) and/or (II) or salt thereof (as theactive ingredient), is intimately admixed with a pharmaceutical carrieraccording to conventional pharmaceutical compounding techniques, whichcarrier may take a wide variety of forms depending of the form ofpreparation desired for administration, e.g., oral or parenteral such asintramuscular. In preparing the compositions in oral dosage form, any ofthe usual pharmaceutical media may be employed. Thus, for liquid oralpreparations, such as for example, suspensions, elixirs and solutions,suitable carriers and additives include water, glycols, oils, alcohols,flavoring agents, preservatives, coloring agents and the like; for solidoral preparations such as, for example, powders, capsules, caplets,gelcaps and tablets, suitable carriers and additives include starches,sugars, diluents, granulating agents, lubricants, binders,disintegrating agents and the like. Because of their ease inadministration, tablets and capsules represent the most advantageousoral dosage unit form, in which case solid pharmaceutical carriers areobviously employed. If desired, tablets may be sugar coated or entericcoated by standard techniques. For parenterals, the carrier will usuallycomprise sterile water, though other ingredients, for example, forpurposes such as aiding solubility or for preservation, may be included.Injectable suspensions may also be prepared, in which case appropriateliquid carriers, suspending agents and the like may be employed.

[0091] Topical formulations included within the present invention,include but are not limited to creams, lotions, multiple emulsions,microemulsions, liposomal creams or gels, gels, solutions, suspensions,ointments, foaming aerosols, hard or soft gelatin capsules, masks,sticks, roll-ons, powders, spray forms, and the like. The topicalformulations may contain, in addition to the active ingredient(s), oneor more non-active components including, but are not limited tochelating agents, buffering agents, colorants, preservatives,fragrances, emulsifiers, surfactants, opacifying agents, emollients,solvents, sunscreens, viscosity modifying agents, antioxidants,moisturizers, permeations enhancers, film formers, and the like.

[0092] Topical formulations for acne treatment included within thepresent invention may also contain one or more of the followingcomponents, including comedolytic/keratolytic agents, antimicrobialagents and steroidal or non-steroidal anti-inflammatory agents.(Comedolytic agents refer to any compound capable of rupturing a comedo.Keratolytic agents refer to any compound capable of breaking apartkeratinocyes resulting in exfoliation of the epidermis.) Suitablecomedolytic/keratolytic agents include, but are not limited toretinoids, salicylic acid, glycolic acid, cetyl betaine, and the like.Suitable antimicrobial agents include, but are not limited to benzoylperoxide, erythromycin, tetracycline, clindamycin, azelaic acid, and thelike. Topical formulations typically contain 0.01-1% active ingredient.

[0093] The pharmaceutical compositions herein will contain, per dosageunit, e.g., tablet, capsule, powder, injection, teaspoonful and thelike, an amount of the active ingredient necessary to deliver aneffective dose as described above. The non-topical pharmaceuticalcompositions herein will contain, per unit dosage unit, e.g., tablet,capsule, powder, injection, suppository, teaspoonful and the like, offrom about 0.03 mg to 100 mg/kg (preferred 0.1-30 mg/kg) and may begiven at a dosage of from about 0.1-300 mg/kg/day (preferred 1-50mg/kg/day). The dosages, however, may be varied depending upon therequirement of the patients, the severity of the condition being treatedand the compound being employed. The use of either daily administrationor post-periodic dosing may be employed.

[0094] Preferably these compositions are in unit dosage forms from suchas tablets, pills, capsules, powders, granules, sterile parenteralsolutions or suspensions, metered aerosol or liquid sprays, drops,ampoules, autoinjector devices or suppositories; for oral parenteral,intranasal, sublingual or rectal administration, or for administrationby inhalation or insufflation. Alternatively, the composition may bepresented in a form suitable for once-weekly or once-monthlyadministration; for example, an insoluble salt of the active compound,such as the decanoate salt, may be adapted to provide a depotpreparation for intramuscular injection. For preparing solidcompositions such as tablets, the principal active ingredient is mixedwith a pharmaceutical carrier, e.g. conventional tableting ingredientssuch as corn starch, lactose, sucrose, sorbitol, talc, stearic acid,magnesium stearate, dicalcium phosphate or gums, and otherpharmaceutical diluents, e.g. water, to form a solid preformulationcomposition containing a homogeneous mixture of a compound of thepresent invention, or a pharmaceutically acceptable salt thereof. Whenreferring to these preformulation compositions as homogeneous, it ismeant that the active ingredient is dispersed evenly throughout thecomposition so that the composition may be readily subdivided intoequally effective dosage forms such as tablets, pills and capsules. Thissolid preformulation composition is then subdivided into unit dosageforms of the type described above containing from 0.1 to about 500 mg ofthe active ingredient of the present invention. The tablets or pills ofthe novel composition can be coated or otherwise compounded to provide adosage form affording the advantage of prolonged action. For example,the tablet or pill can comprise an inner dosage and an outer dosagecomponent, the latter being in the form of an envelope over the former.The two components can be separated by an enteric layer which serves toresist disintegration in the stomach and permits the inner component topass intact into the duodenum or to be delayed in release. A variety ofmaterial can be used for such enteric layers or coatings, such materialsincluding a number of polymeric acids with such materials as shellac,cetyl alcohol and cellulose acetate.

[0095] The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude, aqueous solutions, suitably flavoured syrups, aqueous or oilsuspensions, and flavoured emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles. Suitable dispersing or suspendingagents for aqueous suspensions, include synthetic and natural gums suchas tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinyl-pyrrolidone or gelatin.

[0096] The method of treating disorders mediated by a melanocortinreceptor described in the present invention may also be carried outusing a pharmaceutical composition comprising any of the compounds asdefined herein and a pharmaceutically acceptable carrier. Thenon-topical pharmaceutical composition may contain between about 0.01 mgand 100 mg, preferably about 5 to 50 mg, of the compound, and may beconstituted into any form suitable for the mode of administrationselected. Carriers include necessary and inert pharmaceuticalexcipients, including, but not limited to, binders, suspending agents,lubricants, flavorants, sweeteners, preservatives, dyes, and coatings.Compositions suitable for oral administration include solid forms, suchas pills, tablets, caplets, capsules (each including immediate release,timed release and sustained release formulations), granules, andpowders, and liquid forms, such as solutions, syrups, elixers,emulsions, and suspensions. Forms useful for parenteral administrationinclude sterile solutions, emulsions and suspensions.

[0097] Advantageously, compounds of the present invention may beadministered in a single daily dose, or the total daily dosage may beadministered in divided doses of two, three or four times daily.Furthermore, compounds for the present invention can be administered inintranasal form via topical use of suitable intranasal vehicles, or viatransdermal skin patches well known to those of ordinary skill in thatart. To be administered in the form of a transdermal delivery system,the dosage administration will, of course, be continuous rather thanintermittent throughout the dosage regimen.

[0098] For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water and the like. Moreover, when desired or necessary,suitable binders; lubricants, disintegrating agents and coloring agentscan also be incorporated into the mixture. Suitable binders include,without limitation, starch, gelatin, natural sugars such as glucose orbeta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth or sodium oleate, sodium stearate, magnesiumstearate, sodium benzoate, sodium acetate, sodium chloride and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum and the like.

[0099] The liquid forms in suitably flavored suspending or dispersingagents such as the synthetic and natural gums, for example, tragacanth,acacia, methylcellulose and the like. For parenteral administration,sterile suspensions and solutions are desired. Isotonic preparationswhich generally contain suitable preservatives are employed whenintravenous administration is desired.

[0100] The compound of the present invention can also be administered inthe form of liposome delivery systems, such as small unilamellarvesicles, large unilamellar vesicles, and multilamellar vesicles.Liposomes can be formed from a variety of phospholipids, such ascholesterol, stearylamine or phophatidylcholines.

[0101] Compounds of the present invention may also be delivered by theuse of monoclonal antibodies as individual carriers to which thecompound molecules are coupled. The compounds of the present inventionmay also be coupled with soluble polymers as targetable drug carriers.Such polymers can include polyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamidephenol,polyhydroxy-ethylaspartamidephenol, or polyethyl eneoxidepolylysinesubstituted with palmitoyl residue. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyepsilon caprolactone, polyhydroxy butyeric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates andcross-linked or amphipathic block copolymers of hydrogels.

[0102] Compounds of this invention may be administered in any of theforegoing compositions and according to dosage regimens established inthe art whenever treatment of disorders mediated by a melanocortinreceptor is required.

[0103] The daily dosage of the products may be varied over a wide rangefrom 0.01 to 1,000 mg per adult human per day. For oral administration,the compositions are preferably provided in the form of tabletscontaining, 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0,100, 150, 200, 250 and 500 milligrams of the active ingredient for thesymptomatic adjustment of the dosage to the patient to be treated. Aneffective amount of the drug is ordinarily supplied at a dosage level offrom about 0.01 mg/kg to about 100 mg/kg of body weight per day.Preferably, the range is from about 0.03 to about 10 mg/kg of bodyweight per day. The compounds may be administered on a regimen of 1 to 4times per day.

[0104] Optimal dosages to be administered may be readily determined bythose skilled in the art, and will vary with the particular compoundused, the mode of administration, the strength of the preparation, themode of administration, and the advancement of the disease condition. Inaddition, factors associated with the particular patient being treated,including patient age, weight, diet and time of administration, willresult in the need to adjust dosages.

[0105] The following Examples are set forth to aid in the understandingof the invention, and are not intended, and should not be construed tolimit in any way the invention set forth in the claims which followthereafter.

EXAMPLE 12-(2-methoxyphenyl)-3-phenyl-5-p-tolylamino-[1,2,4]thiadiazol-2-iumCompound #31

[0106]

[0107] Step A:

[0108] A mixture of o-anisidine (15.0 g, 121.8 mmol) and sodium amide(50 wt. % suspension in toluene) (11.40 g, 146.2 mmol) in anhydroustoluene (200 ml) was stirred for 1 hour at room temperature. To themixture was added benzonitrile (9.86 ml, 96.6 mmol) and heated underreflux for 16 hours. The reaction mixture was cooled and 1.0N HCl (150ml) was added to quench the reaction. Activated carbon was added and thereaction mixture was filtered through a Celite pad. The pH of themixture was adjusted to about 14 by addition of 1.0 N NaOH (200 ml). Theaqueous layer was extracted with chloroform (3×150 ml). The combinedorganic layer was dried over anhydrous MgSO₄, and evaporated. Theresulting solid was washed with hexane and dried over the vacuum toyield the product as a pale white solid.

[0109]¹H NMR (300 MHz, CDCl₃)™ 3.83 (s, 3H), 4.79 (s, 2H), 6.96 (m, 3H),7.04 (m, 1H), 7.43 (m, 3H), 7.93 (d, 2H)

[0110] MS (APCI, MH⁺) 227

[0111] Step B:

[0112] A mixture of N-arylbenzamidine (3.0 g, 13.27 mmol), prepared asin Step A, and 4-tolylisothiocyanate (2.18 g, 14.60) in anhydrouschloroform (30 ml) was heated under reflux for 16 hours. The reactionmixture was cooled and the solvent was evaporated. The resulting residuewas purified by flash column chromatography with a mobile phase of 25%hexane in dichloromethane. The combined fractions were evaporated; andthe resulting solid was dried over vacuum to yield the product as ayellow solid.

[0113]¹H NMR (300 MHz, CDCl₃)™ 2.36 (s, 3H), 3.66 (s, 3H), 6.76 (m, 1H),6.97 (t, 1H), 7.17-7.39 (m, 7H), 7.47 (d, 2H), 7.60 (d, 2H), 8.20 (s,1H), 14.18 (s, 1H)

[0114] MS (ES, MH⁺) 376.29

[0115] Step C:

[0116] To the solution of thiourea (2.90 g, 7.73 mmol), prepared as inSTEP B, in anhydrous chloroform (15 ml) was slowly added bromine (438μl, 8.51 mmol). After stirring for 16 hours, the solvent was evaporated.The resulting solid was washed with anhydrous ethyl ether. The crudeproduct was re-crystallized from 20% water in ethanol to yield theproduct as a yellow solid.

[0117]¹H NMR (300 MHz, CDCl₃)™ 2.39 (s, 3H), 3.66 (s, 3H), 6.96 (d, 1H),7.06 (t, 1H), 7.20-8.07 (m, 7H), 7.61 (d, 2H), 7.80 (d, 2H), 12.40 (s,1H)

[0118] MS (ES, MH⁺) 374.25

EXAMPLE 22-(2-methoxyphenyl)-3-(2-methoxyphenyl)-5-phenylamino-[1,2,4]-thiadiazol-2-iumCompound #74

[0119]

[0120] Step A:

[0121] A mixture of o-anisidine (13.5 g, 110.0 mmol) and sodium amide(50 wt. % suspension in toluene) (9.40 g, 120.0 mmol) in anhydroustoluene (200 ml) was stirred for 1 hour at room temperature. To themixture was added 2-methoxybenzonitrile (16 ml, 131.0 mmol) and thereaction mixture was then heated under reflux for 16 hours. The reactionmixture was cooled and 1.0N HCl (150 ml) was added to quench thereaction. Activated carbon was added and the reaction mixture wasfiltered through a Celite pad. The pH of the mixture was adjusted toabout 14 by addition of 1.0 N NaOH (200 ml). The aqueous layer wasextracted with chloroform (3×150 ml). The combined organic layer wasdried over anhydrous MgSO₄, and evaporated. The resulting solid waswashed with hexane and dried over the vacuum to yield the product as apale white solid.

[0122] MS (APCI, MH⁺) 257

[0123] Step B:

[0124] A mixture of N-arylbenzamidine (15.5 g, 60.6 mmol), prepared asin STEP A and phenylisothiocyanate (8.70 mL, 72.7 mmol) in anhydrouschloroform (30 ml) was heated at 45° C. for 16 hours. The reactionmixture was cooled and the solvent was evaporated. The resulting residuewas purified by flash column chromatography with a mobile phase of 25%hexane in dichloromethane. The combined fractions were evaporated andthe resulting solid was dried over vacuum to yield the product as ayellow solid.

[0125] MS (ES, MH⁺) 391.50

[0126] Step C:

[0127] To a solution of thiourea (12.95 g, 33.1 mmol), prpeared as inSTEP B, in anhydrous chloroform (15 ml) was slowly added bromine (1.78mL, 34.75 mmol). After stirring for 16 hours, the solvent wasevaporated. The resulting solid was washed with anhydrous ethyl ether.The crude product was re-crystallized from 20% water in ethanol to yieldthe product as a yellow solid.

[0128] MS(ES, MH⁺) 390.1

[0129] Following the procedures disclosed herein, representativecompounds of formula (I) of the present invention were prepared, aslisted in Table 1. TABLE 1

ID No. R¹ R² R³ R⁴ 1 4-methylphenyl phenyl H 4-methoxyphenyl 24-methylphenyl phenyl H phenyl 3 4-methylphenyl phenyl H 2-methoxyphenyl4 4-methylphenyl phenyl H 4-methylphenyl 5 4-methylphenyl phenyl H2-methylphenyl 6 4-methylphenyl phenyl H 4-chlorophenyl 7 4-methylphenylphenyl H 2-chlorophenyl 8 2-methylphenyl phenyl H phenyl 92-methylphenyl phenyl H 4-methoxyphenyl 10 2-methylphenyl phenyl H2-methoxyphenyl 11 2-methylphenyl phenyl H 4-methylphenyl 122-methylphenyl phenyl H 2-methylphenyl 13 2-methylphenyl phenyl H4-chlorophenyl 14 2-methylphenyl phenyl H 2-chlorophenyl 154-chlorophenyl phenyl H phenyl 16 4-chlorophenyl phenyl H4-methoxyphenyl 17 4-chlorophenyl phenyl H 2-methoxyphenyl 184-chlorophenyl phenyl H 4-methylphenyl 19 4-chlorophenyl phenyl H2-methylphenyl 20 4-chlorophenyl phenyl H 4-chlorophenyl 214-chlorophenyl phenyl H 2-chlorophenyl 22 phenyl phenyl H phenyl 23phenyl phenyl H 4-methoxyphenyl 24 phenyl phenyl H 2-methoxyphenyl 25phenyl phenyl H 4-methylphenyl 26 phenyl phenyl H 2-methylphenyl 27phenyl phenyl H 4-chlorophenyl 28 2-methoxyphenyl phenyl H phenyl 292-methoxyphenyl phenyl H 4-methoxyphenyl 30 2-methoxyphenyl phenyl H2-methoxyphenyl 31 2-methoxyphenyl phenyl H 4-methylphenyl 322-methoxyphenyl phenyl H 2-methylphenyl 33 2-methoxyphenyl phenyl H4-chlorophenyl 34 2-methoxyphenyl phenyl H 2-chlorophenyl 354-methoxyphenyl phenyl H phenyl 36 4-methoxyphenyl phenyl H4-methoxyphenyl 37 4-methoxyphenyl phenyl H 2-methoxyphenyl 384-methoxyphenyl phenyl H 4-methylphenyl 39 4-methoxyphenyl phenyl H2-methylphenyl 40 4-methoxyphenyl phenyl H 4-chlorophenyl 414-methoxyphenyl phenyl H 2-chlorophenyl 42 2-chlorophenyl phenyl Hphenyl 43 2-chlorophenyl phenyl H 4-methoxyphenyl 44 2-chlorophenylphenyl H 2-methoxyphenyl 45 2-chlorophenyl phenyl H 4-methylphenyl 462-chlorophenyl phenyl H 2-methylphenyl 47 2-chlorophenyl phenyl H4-chlorophenyl 48 2-chlorophenyl phenyl H 2-chlorophenyl 49 phenylphenyl H 2-chlorophenyl 50 4-methylphenyl phenyl CH₃ 4-methoxyphenyl 51phenyl phenyl H 4-methoxybenzyl 52 phenyl phenyl H 2-methoxybenzyl 53phenyl phenyl H 4-methylbenzyl 54 phenyl phenyl H 2-methylbenzyl 55phenyl phenyl H 4-chlorobenzyl 56 phenyl phenyl H 2-chlorobenzyl 574-methoxyphenyl 4-methoxyphenyl H phenyl 58 4-methoxyphenyl4-methoxyphenyl H 4-methoxyphenyl 59 4-methoxyphenyl 4-methoxyphenyl H2-methoxyphenyl 60 4-methoxyphenyl 4-methoxyphenyl H 4-methylphenyl 614-methoxyphenyl 4-methoxyphenyl H 2-methylphenyl 62 4-methoxyphenyl4-methoxyphenyl H 4-chlorophenyl 63 4-methoxyphenyl 4-methoxyphenyl H2-chlorophenyl 64 4-methoxyphenyl 4-methoxyphenyl H 3-pyridyl 652-methoxyphenyl 4-methylphenyl H phenyl 66 2-methoxyphenyl4-methylphenyl H 4-methoxyphenyl 67 2-methoxyphenyl 4-methylphenyl H2-methoxyphenyl 68 2-methoxyphenyl 4-methylphenyl H 4-methylphenyl 692-methoxyphenyl 4-methylphenyl H 2-methylphenyl 70 2-methoxyphenyl4-methylphenyl H 4-chlorophenyl 71 2-methoxyphenyl 4-methylphenyl H2-chlorophenyl 72 2-methoxyphenyl 4-methylphenyl H 3-pyridyl 732-methoxyphenyl phenyl H 3-pyridyl 74 2-methoxyphenyl 2-methoxyphenyl Hphenyl 75 2-methoxyphenyl 2-methoxyphenyl H 4-methoxyphenyl 762-methoxyphenyl 2-methoxyphenyl H 2-methoxyphenyl 77 2-methoxyphenyl2-methoxyphenyl H 4-methylphenyl 78 2-methoxyphenyl 2-methoxyphenyl H2-methylphenyl 79 2-methoxyphenyl 2-methoxyphenyl H 4-chlorophenyl 802-methoxyphenyl 2-methoxyphenyl H 2-chlorophenyl 81 2-methoxyphenyl2-methoxyphenyl H 3-pyridyl 84 phenyl phenyl H benzyl 85 2-methoxyphenyl2-methoxyphenyl H 4-bromophenyl 86 2-methoxyphenyl 2-methoxyphenyl H2,6-difluoro phenyl 87 2-methoxyphenyl 2-methoxyphenyl H 2-chloro-6-methylphenyl 88 2-methoxyphenyl 2-methoxyphenyl H 3,5-difluoro phenyl

EXAMPLE 32-(2-methoxyphenyl)-3-(2-methoxyphenyl)-5-phenylamino-{1,2,4]-thiadiazoleCompound #89

[0130]

[0131] To a solution of the compound prepared as in Step B of Example 2(0.921 g, 2.36 mmol) in anhydrous chloroform (10 mL) was addedN-chlorosuccinimide (326 mg, 2.71 mmol). The reaction mixture was thenstirred for 16 hours, and then stopped and washed twice with aqueousNaHCO₃. The organic layer was dried over magnesium sulfate and theremaining solvent removed under vacuum to yield the title product as asolid.

[0132] MS (ES, MH+) 390.1

[0133] Following the procedures disclosed herein, representativecompounds of formula (II) of the present invention were prepared, aslisted in Table 2. TABLE 2

ID No. R¹ R² R⁴ 82 4-methylphenyl phenyl phenyl 83 4-methylphenyl phenyl4-methoxyphenyl 89 2-methoxyphenyl 2-methoxyphenyl phenyl 902-methoxyphenyl 2-methoxyphenyl 2,6-difluoro phenyl 91 2-methoxyphenyl2-methoxyphenyl 2-chloro-6- methylphenyl 92 2-methoxyphenyl2-methoxyphenyl 3,5-difluoro phenyl

[0134] Unless otherwise noted, NMR spectra, were measured on a BrukerAvance 300 MHz NMR spectrometer. Unless otherwise noted, molecularweights were measured using a Micromass LC platform electrospray massspectrometer, as listed in Table 3. TABLE 3 ID No MW 1 (as +ion) MW 2(w/Br−) Meas. MW 1 374.49 454.39 374.0 2 344.46 424.36 344.0 3 374.49454.39 374.3 4 358.49 438.39 358.3 5 358.49 438.39 358.4 6 378.91 458.81378.1, 380.3 7 378.91 458.81 378.2, 380.2 8 344.46 424.36 344.3 9 374.49454.39 374.2 10 374.49 454.39 374.2 11 358.49 438.39 358.3 12 358.49438.39 358.3 13 378.91 458.81 378.2, 380.2 14 378.91 458.81 378.2, 380.215 364.88 444.78 346.2, 366.2 16 394.90 474.81 394.1, 396.1 17 394.90474.81 394.1, 396.1 18 378.91 458.81 378.2, 380.2 19 378.91 458.81378.2, 380.2 20 399.32 479.23 398.1, 400.1 21 399.32 479.23 398.1, 400.022 330.43 410.34 330.3 23 360.46 440.37 360.3 24 360.46 440.37 360.3 25344.46 424.37 344.4 26 344.46 424.37 344.3 27 364.88 444.78 364.2, 366.228 360.46 440.37 360.3 29 390.49 470.39 390.2 30 390.49 470.39 390.2 31374.49 454.39 374.3 32 374.49 454.39 374.3 33 394.90 474.81 394.1, 396.134 394.90 474.81 394.1, 396.1 35 360.46 440.37 360.3 36 390.49 470.39390.3 37 390.49 470.39 390.3 38 374.49 454.39 374.3 39 374.49 454.39374.3 40 394.90 474.81 394.2, 396.2 41 394.90 474.81 394.2, 396.2 42364.88 444.78 364.3, 366.3 43 394.90 474.81 394.2, 396.2 44 394.90474.81 394.2, 396.2 45 378.91 458.81 378.2, 380.2 46 378.91 458.81378.2, 380.2 47 399.32 479.23 398.1, 400.1 48 399.32 479.23 398.1, 400.149 364.88 444.78 364.2, 366.2 50 388.51 537.58 388.3 51 374.49 454.39374.3 52 374.49 454.39 374.3 53 358.49 438.39 358.4 54 358.49 438.39358.4 55 378.91 458.81 378.3, 380.3 56 378.91 458.81 378.3, 380.3 57390.49 470.39 390.1 58 420.51 500.42 420.1 59 420.51 500.42 420.1 60404.51 484.42 404.1 61 404.51 484.42 404.0 62 424.93 504.83 424.0, 426.063 424.93 504.83 424.0, 426.0 64 391.47 471.38 391.0 65 374.49 454.39374.2 66 404.51 484.42 404.2 67 404.51 484.42 404.1 68 388.51 468.42388.3 69 388.51 468.42 388.2 70 408.93 488.84 408.6, 410.0 71 408.93488.84 408.1, 410.0 72 375.47 455.38 375.2 73 361.45 441.35 361. 74390.49 470.39 390.2 75 420.51 500.42 420.2 76 420.51 500.42 420.2 77404.51 484.42 404.1 78 404.51 484.42 404.1 79 424.93 504.84 424.1, 426.180 424.93 504.84 424.1, 426.1 81 391.47 471.38 391.1 82 343.45 344.3 83373.48 374.3 84 344.46 424.36 344.3 85 469.38 549.29 86 426.5 506.4426.3 87 439.0 518.9 438.3, 440.3 88 426.5 506.4 426.2 89 389.5 390.1 90425.5 426.2 91 437.9 438.3, 440.3 92 425.5 426.2

EXAMPLE 4 Melanocortin MC-4 Receptor Binding Assay

[0135] Melanocortin [MC-4]-membrane [purchased from Receptor BiologyInc] was coupled to wheat germ agglutinin coated polyvinyltoluene-Scintillation Proximity Assay beads [purchased from AmershamPharmacia Inc.] for 30 min at 25° C. Into each well of a 96-well Optiplate [purchased from Packard, CA], 2.5 μg of membrane and 0.25 mg ofbeads were mixed in a volume of 100 μL media. The media was 50 mM HEPES,pH 7.4 containing 0.1% bovine serum albumin, 2 mM CaCl₂, 2 mM MgCl₂ andprotease inhibitors. Test compounds (1.5 μL) at 1 mM in 30% DMSO-50 mMHEPES, pH 7.4 buffer was added to separate wells on the plate.Radioactive ligand ¹²⁵I-NDP-melanocyte stimulating hormone [NEN, 2000Ci/mmol] was added to each well (48.5 μL per well, 40 pM finalconcentration). The plate was then sealed and let stand for 16 hr at 25°C. NDP-Melanocyte stimulating hormone peptide and α-melanocytestimulating hormone peptide [purchased from Palomar Research Inc, 1 μM]were used as reference inhibitor compounds to define non-specificbinding (N). Total binding (T) was defined using 30% DMSO-50 mM HEPES,pH 7.4 buffer. Bound radioactivity for each well (Y), measured at countsper minute (cpm) was measured in a TopCount [Packard, CA]. Percentinhibition was calculated as:

[(T−Y)/(T−N)]*100%

EXAMPLE 5 Cyclic-Adenosine Monophosphate [cAMP] Stimulation Assay

[0136] Human Bowes melanoma cells expressing human melanocortin MC-4receptor were grown to confluence in a 24-well culture plate. The growthmedium was discarded and to each well was added 0.5 mL of Hank'ssolution. Test compounds were added to wells of a 96 well plate.NDP-melanocyte stimulating hormone peptide (1 μM) was added to thepositive control wells while negative control wells received vehicle of30% DMSO-50 mM HEPES, pH 7.4 buffer. The plate was incubated at 37° C.and 5% CO₂ for 30 min. The supernatant was discarded and the cells werewashed twice with Hank's solution. Ethanol (80%, 0.5 mL) was added toeach well and the plates were incubated at 4° C. for 30 min. Cyclic AMPcontent was measured using the NEN Flashplate kit [NEN]. A melanocortinreceptor agonist is defined as a test compound which resulted in anincrease in cAMP production in this assay.

EXAMPLE 6 G-Protein Activation Assay

[0137] For each assay, membranes expressing the melanocortin MC-4receptor (5 μg) were incubated for 5 min at 25° C. with 0.5 nM ³⁵S-GTPγSin 100 μL of 25 mM HEPES buffer, pH7.5 containing 100 mM NaCl, proteaseinhibitors, 0.5 μM GDP, 5 mM 2-mercaptoethanol, 1 mM MgCl₂ together withtest compound, 1 μM of NDP-melanocyte stimulating hormone or acombination of NDP-melanocyte stimulating hormone and test compound.Basal ³⁵S-GTPγS binding was defined by 10 mM HEPES, pH 7.4 buffercontaining 30% DMSO. The reaction was terminated by addition of 50 μl oftermination buffer containing 25 mM HEPES, pH7.5, 20 mM MgCl₂, proteaseinhibitors, 100 μM GDP, 100 μM GTP, 5 mM 2-mercaptoethanol withdetergents (0.5% digitonin, 0.2% sodium deoxycholate, and 0.5% NP-40).The membranes were solubilized for 30 minutes at 25° C. The ³⁵S-GTPγSbound Gαs protein was immunoprecipitated using anti-Gαs (0.5 μg) thatlinked to anti-rabbit IgG protein A conjugated SPA. Bound radioactivitywas measured in a Topcount [Packard]. Non-specific ³⁵S-GTPγS binding wasdefined by ³⁵S-GTPγS immunoprecipitated by normal rabbit IgG (0.5 μg).Basal binding (B) = Mean counts/minute (cpm) immunoprecipitated by anti-Gαs. Non-specific binding (NSB) = Mean cpm immunoprecipitated by normalrabbit IgG. Specific basal binding (SB) = B-NSB Cpm in each well = C Netcpm in each well (N) = C-NSB % stimulation = [(N − SB)/SB] × 100%

[0138] The procedures described above for the melanocortin MC-4 receptorwere repeated for the melanocortin MC-3 receptor. Following theprocedures described, representative compounds of the present inventionwere tested for binding in the MC-4 and/or MC-3 assay, as listed inTable 4. TABLE 4 IC₅₀ MC-4 (μM) IC₅₀ MC-4 (nM) ID No. (Filtration) (SPA)1 1.1 174 2 1.5 234 3 0.7 159 4 inactive 297 5 1.3 207 6 2.5 293 7 2.2218 8 1.4 201 9 1.1 217 10 2.3 130(90) 11 2.4 243 12 insoluble insoluble13 3.4 347 14 5.6 234 15 4.5 482 16 4.3 424 17 7.7 351 18 6.0 463 19 3.9460 20 3.5 636 21 7.8 392 22 124 23 124 24 76 25 57 26 63 27 89 28 68 2948 30 103 31 22 32 48 33 91 34 46 35 100 36 79 37 72 38 159 39 146 40133 41 483 42 482 43 237 44 89 45 246 46 368 47 874 48 444 49 96 5030,000 51 1,000 52 1,000 53 1,000 54 800 55 800 56 3,000 57 inactive 58inactive 59 inactive 60 inactive 61 inactive 62 inactive 63 1,000 641,200 65 114 66 120 67 130 68 110 69 139 70 566 71 234 72 155 73 725 74194 75 103 76 332 77 4.4 78 99 79 216 80 378 81 672 82 1.5 826 83 1.9833 84 82 nm

EXAMPLE 7 Rodent Feeding: Food Intake in Food-Deprived Rats (MC-4)

[0139] Male Long-Evans rats (180-200 grams) were housed individually andmaintained on a once-a-day feeding schedule (i.e. 10 a.m. until 4 p.m.)for five days following quarantine to allow the animals to acclimate tofeeding on powdered chow (#5002 PMI Certified Rodent Meal) during theallotted time. The chow was made available in an open jar, anchored inthe cage by a wire, with a metal follower covering the food to minimizespillage. Water was available ad-libitum.

[0140] Animals were fasted for 18 hours prior to testing. At the end ofthe fasting period, animals were administered either a test compound orvehicle. Vehicle and test compound were administered either orally (5mL/kg) 60 minutes prior to the experiment, subcutaneously (1 mL/kg) 30minutes prior to the experiment, or intraperitoneally (1 mL/kg) 30minutes prior to the experiment. Test compounds were administered orallyas a suspension in aqueous 0.5% methylcellulose-0.4% Tween 80, orintraperitoneally as a solution or suspension in PEG 200; compoundconcentrations typically ranged from 1 mg/kg to 100 mg/kg, preferablyfrom 10-30 mg/kg. Food intake was measured at 2, 4, and 6 hours afteradministration by weighing the special jar containing the food beforethe experiment and at the specified times. Upon completion of theexperiment, all animals were given a one-week washout period beforere-testing.

[0141] Following the procedure described above, select compounds of thepresent invention were tested to measure the effect on food intake infasted rats, as listed in Table 5 and 6. TABLE 5 [mg/kg], Food IntakeFood Intake ID No. Route 0-2 hrs 2-6 hrs PEG-200 ip 8.25 g 13.38 g 1 10μ, ip 7.29 g  8.43 g

[0142] TABLE 6 Change in Change in [mg/kg], Food Intake Food Intake IDNo. Route 0-2 hrs (%) 2-6 hrs (%) MCT Control po 0 0 PEG-200 ip 0 0Control  1 10, ip −11.60% −37.00%  1 30, po −21.2 −6.7 84 10, ip −7−24.5 84 10, ip 3.9 −17.8 84 30, po −7 32 26 10, ip −12.7 −32.3 27 30,ip −27.4 −29.1 29 30, po −26.3 −3.7 29 10, ip −62.3 −70.7 31  3, ip−37.8 −50 31  1, ip −20.6 −71.2 31 30, po −23.6 31.5 31 10, po −10.139.7 31  3, po −9 52.1 31  1, po 1.2 19.5 32 10, ip −29.6 −60.2 32 30,po −12.5 −15 32 10, po −20 −1 32  3, po −11.5 31.17 32  1, po −13.8 2634 10, ip −38 −72 34 30, po −7.5 2 34 10, po −1.3 −6 49 30, ip −20.6−21.2

EXAMPLE 8 Neurite Cell Outgrowth Assay

[0143] Cell Culture:

[0144] Dissociated hippocampal and cortical cell cultures wereestablished from embryonic day 18 rat fetuses as described by Mattson,M. P., Barger, S. W., Begley, J, and Mark, R. J., Methods Cell Biol.,1994, 46:087-216. Briefly, fetuses were removed via cesarean sectionfrom pregnant moms (Sprague-Dawley) and anesthetized with halothaneaccording to the AVMA Panel on Euthanasia. Pups were decapitated and thebrains were removed and placed in HEPES-buffered Hank's Balanced Saltsolution (HBSS; Gibco). The hippocampi and cortices were dissected outand pooled according to tissue-type. Tissue was trypsinized for 15 min(1 mg/ml trypsin-HBSS; Worthington), rinsed with fresh HBSS, incubatedin trypsin inhibitor (1 mg/ml; Sigma) for 5 min, rinsed again with freshHBSS and then triturated in 1 ml fresh HBSS with a fire-polished glasspipette. Dissociated cells were seeded at 30,000 cells/well ontopoly-D-lysine coated 96-well plates (Collaborative BioScience). Eachwell contained 100 μl of Eagle's Minimal Essential Media (MEM; Gibco)supplemented with 26 mM NaHCO₃ (Sigma), 56 mM glucose (Sigma), 15 mM KCl(Sigma), 1 mM sodium pyruvate (Sigma), 1.1 mM L-glutamine (Sigma), 10%(v/v) heat-inactivated fetal bovine serum (Hyclone), and 0.001%gentamicin sulfate (Sigma) (pH 7.4). Cells were allowed to attach for 24h in a humidified 37° C. 5% CO₂ incubator before experimental treatment.The culture media was aspirated and exchanged with fresh media every 3days.

[0145] Assay:

[0146] Twenty-four hours after plating, cultures were treated withvehicle (PBS+0.1% BSA), alpha-melanocyte stimulating hormone (α-MSH) ortest compound (diluted in DPBS). Each treatment condition was run inquadruplicate. On the third day in culture, the media was aspirated offand replaced with fresh media and test compound. At one week in culture,the cells were fixed with 10% phosphate-buffered formalin for 15 min,then rinsed with DPBS (Sigma) and placed in blocking serum for 30 min(horse serum; 1:50 dilution in DPBS; Vector Labs). The cultures wererinsed again with DPBS and then incubated in primary antibody for 2 hr(microtubule-associated protein-2 (MAP-2) is a selective marker fordendritic processes; anti-mouse monoclonal (Chemicon); 1:1000 dilutionof MAP-2 in antibody diluent (Zymed)). Negative control wells wereincubated in antibody diluent alone. Background signal was determined byblank wells (cell-free) incubated with or without antibody. Cultureswere rinsed again with DPBS and then placed in fluorescein for 1 hr(FITC; anti-mouse IgG; rat adsorbed; 1:50 dilution in DPBS; VectorLabs). Cultures were rinsed a final time with DPBS and the plates werethen read on a Cytofluor 4000 fluorescence plate reader. Neuriteoutgrowth was expressed as percent change from control (vehicle).

[0147] Selected compounds of the instant invention were tested in theabove assay with results as listed in Table 7. The data are expressed aspercent change over the vehicle response. All compounds were screened at50 nM. The abbreviation NA indicates no change/not active; theabbreviation ND indicates a compound not tested/response not determined.TABLE 7 Neurite Outgrowth ID No. Hippocampal Cells Cortical CellsVehicle 19%  4% 1  6% NA 2 18% 18% 3 17% 23% 4 20% 21% 5 28%  9% 6 23%24% 7 NA 11% 8 NA 12% 9 NA NA 10  7% 11% 11  9% 10% 12 28% 20% 13 29%32% 14 30% 19% 15 18% 31% 16  8% 18% 17  8% 17% 18 17% 17% 19 22% NA 2017% NA 21 27%  2% 22 NA 30% 23 10% 20% 24 10% 16% 25 NA 23% 26 16% 47%27 17% 52% 28 NA 25% 29 NA  8% 30 NA NA 31 NA 16% 32 NA  6% 33 NA 21% 34NA 22% 35 NA 28% 36 NA 16% 37 NA 26% 38 NA NA 39 NA ND 40 26% NA 41 36% 5% 42 26% NA 43 30% 37% 44 43% 19% 45 46% 25% 46 40% 19% 47 20% 13% 48NA 19% 49 16% 51% 50 46% NA 51 74% 28% 52 65% NA 53 67% NA 54 45% NA 5519% NA 56 33% NA 57  9% NA 58 72% 10% 59 61% 21% 60 66% 14% 61 66% 17%62 13% 13% 63 20% 17% 64 22% 12% 82 14% 15% 83 11%  9% 84 ND 17%

[0148] The data above show that cultures treated with select compoundsof the present invention resulted in a significant increase in neuriteoutgrowth as measured by MAP2-FITC immunofluorescence. A comparisonbetween the test compounds and α-MSH indicates that many of the testcompounds were superior to α-MSH in promoting neurite outgrowth at theconcentration tested. In addition, several of the test compoundsdisplayed selective effects on neurite outgrowth in hippocampal orcortical cells.

EXAMPLE 9 In vivo Facial Nerve Compression Model

[0149] The ability of test compound to provide neuro-protective orneuro-regenerative effects was investigated in a facial nervecompression model. Facial nerve motor axons arise exclusively fromneurons within the pons in a well-defined nucleus. Facial nervecompression results in retrograde reactions proximal to the lesion siteand Wallerian degeneration at its distal part, which causes diminishedwhisker movement on the lesioned side.

[0150] Male Long-Evans rats (150-180 g) were anesthetized with 3-5%isoflorane for induction and 2% for maintenance during the surgicalprocedures. The right facial nerve was exposed and compressed withforceps for 30 sec at its exit from the stylomastoid foramen. The leftfacial nerve was sham-operated and served as an internal control. Nervecompression causes paralysis of whisker muscles, hence the reducedwhisker movement on the lesioned side, which is observed immediatelyafter recovery from anesthesia. The following morphologicalabnormalities associated with the functional deficit were observed:

[0151] (1) an increase in the number of perineuronal glial cells in thefacial nucleus of the lesioned side, with the increased observed to peakaround D3-6;

[0152] (2) a thinner myelin sheath and less myelin basic proteinstaining in the compressed facial nerve approximately one week after thelesion;

[0153] (3) morphological alterations around the N-M junction and whiskerfollicles regions and gradually degeneration of motor neurons in thefacial nuclei.

[0154] After recovery from anesthesia, the rats were randomly dividedinto groups for dosing with vehicle, αMSH or test compound, with 6animals per group. αMSH (s.c., 70 ug/each 48 hr) was used as a positivecontrol. Test compounds were dosed p.o. at 20 mg/kg bid for 14 days.Restoration of whisker movement was monitored daily after the operationusing two criteria:

[0155] (1) frequency of whisker movement on the lesioned side relativeto the the opposite side (sham-operated) which served as the baselinecontrol

[0156] (2) semi-quantitative measurements (0 to 4+) on strength of thewhisker muscles, characterized based on observation of the percentage ofmoved whiskers, muscle tone of whisker muscles, and the position of thenose. For all observations, the experimental design was blind to thebehavioral observer.

[0157] The results of behavioral assessment showed that both testcompounds, compounds #31 and #84, accelerated the recovery time torestore whisker muscle movement in the lesioned rats as compared to thevehicle controls (p<0.05). The recovery rate of the whisker movement wasexpressed as percentage of its own internal control (sham-operated), aslisted in Table 8. TABLE 8 Functional Recovery of Whisker Movement afterOral Administration of Compound #31 and #84 in Facial Nerve CompressionModel Percent Recovery D9 D10 D11 D12 D13 D14 Unlesioned Site 100  100100 100 100 100 Vehicle 0 5.0 ± 6.8 27.6 ± 15.9 72.5 ± 21.2  86.4 ± 14.591.3 ± 8.3  α-MSH 2.0 ± 2.8 24.6 ± 15.8 60.1 ± 19.3 93.8 ± 14.0 98.1 ±5.3 100 ± 0.0 Cmpd #31 0 3.5 ± 3.1 67.8 ± 9.5  98.5 ± 3.7   100 ± 0.0100 ± 0.0 (246377) Cmpd #84 0 4.8 ± 4.3 35.1 ± 12.9 90.0 ± 10.9 98.3 ±4.1 100 ± 0.0 (153791)

EXAMPLE 10 In vitro Assay: Measurement of Regulation of Sebaceous LipidSynthesis

[0158] Step A: Preparation of a Feeder Layer

[0159] Semiconfluent cultures of 3T3 mouse fibroblasts (Swiss Albinomouse, ATCC CCL-92) were treated with mitomycin C (4 μg/ml) for 3 hours,trypsinized and seeded at a density of 2.5×10⁵/9.5 cm² tissue cultureplate in Dulbeccos Minimal Essential Medium (DMEM) containing 10%Colorado Calf Serum, PNC (100 U/ml), STM (100 μg/ml), L glutamine (0.3mg/ml), sodium pyruvate (1 mM) and nonessential amino acids (100 μM).The cells were incubated at 37° C. for 24 hours prior to their use as afeeder layer for sebocytes.

[0160] Step B: Isolation of Human Sebocytes

[0161] Human sebocytes were isolated from Dermatome shavings ofpostoperative pieces of human skin at 0.4-0.8 mm depths (this part ofthe skin was previously shown to be enriched in sebaceous glands).Shavings so obtained were treated with 1% Dispase in Iscoves mediumcontaining 10% serum for 20 min at 37° C. The tissue was then placed in0.3% trypsin/1% EDTA in Phosphate Buffered Saline (PBS) for 10 minutesat 37° C. Following this incubation the cells were gently scraped fromthe tissue in Growth medium (GM) containing DMEM/F12 media mixture(3:1), supplemented with 8% heat inactivated FBS, 2% heat inactivatedhuman serum (HS),1 mM sodium pyruvate, epidermal growth factor (10ng/ml), insulin (10 μg/ml), hydrocortisone (0.4 μg/ml) and +/−choleratoxin (100 μg/ml), L-glutamine and antibiotics. Cells so obtained werefiltered through nylon mesh (100μ pore size), centrifuged at 750 RPM,re-suspended in GM and counted.

[0162] Step C: Cultures of Human Sebocytes

[0163] Resultant cells from the above isolation procedure were plated onthe 3T3 feeder layers at 2×10⁵/9.5 cm² in growth medium and maintainedat 37° C. and 5% CO₂ for 3 days (Phase I). Following the initial growthperiod they were transferred to a transition medium (TM) that consistedof DMEM/F12 media supplemented with 1 mM sodium pyruvate, insulin (10μg/ml), transferrin (6.7 ng/ml) and selenium (5.5 μg/ml) (ITS), 2% heatinactivated FBS and 2% heat inactivated human serum as well as+/−cholera toxin (ch.t.) (100 μg/ml), L-glutamine and antibiotics (PhaseII). Three days later the cells were changed to differentiation medium(DM), DMEM/F12 supplemented with ITS, 3,3′,5-triido-L-thyronine sodium(3 nM), 1% (v/v) trace element mix and the choice of differentiationagent i.e. bovine pituitary extract (10 μg/ml). This medium was changedevery 3 days (Phase III).

[0164] Step D: Testing Stimulators or Inhibitors of SebocyteDifferentiation and Lipid Production

[0165] Hormones, mixture of hormones i.e. bovine pituitary extract orcompounds to be tested were added to the culture at the beginning ofphase III. Two criteria were used to evaluate the effect of thesematerials on sebaceous cultures: 1) visual observations and 2)evaluation of sebaceous lipid accumulation and synthesis. The evaluationof lipid accumulation completed using the Nile red method. This methodrelies on visualization of neutral lipids by Nile red and quantitationby reading of fluorescence at 535 nm excitation, 580 nm emission using aplate reader. The lipid synthesis was evaluated by radioactive labelingusing ¹⁴C acetate and quantified by Bio Rad Phosphoimager (MolecularImager, FX) using 4.1 Software.

[0166] Step E: Visual Observations & Nile Red Evaluation of LipidAccumulation

[0167] Morphological evaluation of lipid accumulation was easilyrecognized since the cells enlarged and displayed lipid granules that inbright field light microscopy appeared as yellowish circles in thecells. Quantitation of accumulation/inhibition of neutral lipids insebocytes was accomplished by Nile red binding assay. Briefly, followingexposure of sebocytes to test compounds, the cells were allowed tointeract with 1 μM Nile red in Hanks buffered saline solution containingDMSO and Pluronic F127. After 4 hours of incubation, washing andincubation overnight, the fluorescence was read at 535 excitation and580 emission using a fluorescence plate reader. To determine whether thecompounds had an inhibitory effect on cell growth, cell counts wereperformed.

[0168] Following the procedure described above, select compounds of thepresent invention were tested for visual and Nile red evaluation oflipid accumulation, with results as listed in Table 9. TABLE 9 ID % Inh% Inh Visual* Visual* MC5-R No. 0.4 μM 0.8 μM 0.4 μM 0.8 μM IC₅₀ 74 72100  +++ ++++ 154 nM 76 48 88 ++ +++ 317 nM 80 61 91 ++ ++++ 138 nM 67N.T. N.T. ++ +++ 246 nM 50  0  0 0 0 No binding 84  0  0 0 0 No binding

[0169] Step F: Evaluation of Sebaceous Lipid Synthesis by SebaceousCells

[0170] At day 11 of the culture, sebocytes were labeled with ¹⁴C acetateat a final concentration of 2 μCi/ml for 24 hours in serum free culturemedium. The cells were than scraped from plates and frozen at −80° C. inglass vials. Lipid extraction was completed using the Bligh-Dyer method(Bligh, E. G. and Dyer, W. J., Can. J. Biochem. Physiol., 1959, 37, pp911-916) with slight modification as detailed herein. Briefly, cellswere homogenized in a 2:1 chloroform-methanol mixture, in the presenceof KCl. The organic phase was removed from the mixture, the separatedlipids were dried under argon and spotted to high performance thin layerchromatography (HPTLC) plates. The plates were developed by threeseparate mobile phases. The first was hexane (to the top of the plate),followed by toluene (to the top) and finally a 70:30:1 mixture ofhexane:ether:acetic acid (half way up the plate—10 cm). The plates werethan exposed to radiographic film for visualization of radioactive lipidspecies. For visualization of unlabeled lipids the plates were sprayedwith 8% cupric acid and charred on a hot plate. Quantitation of theresults was done by Image Pro Plus 3.0 (Media Cybernetics, SilverSprings, Md.).

[0171] Following the procedure described above, select compounds of thepresent invention were tested for their inhibitory effect ondifferentiation of human sebocytes. Visually, the stained cell culturestreated with compound #74 showed complete disappearance of lipidgranules in sebocyte cultures following a seven day treatment. The samecells examined for lipid synthesis revealed inhibition of squalene,cholesterol esters and wax esters, as measured by radioactively labeledlipids separated by HPTLC. The cell panels were quantified bymeasurement of the intensity of bands using Image Pro Plus (version5.0). % inhibition was calculated based on the difference betweentreated samples and vehicle treated controls, with results as listed inTable 10. TABLE 10 Cell % Inh @ % Inh @ Lipid Inducer Sex 0.4 μM 0.6 μMSqualene Cholera toxin & Bovine F/M 100/100 100/100 pituitary extractCholesterol Cholera toxin & Bovine F/M 85/64 88/76 ester pituitaryextract Unknown Cholera toxin & Bovine F/M 75/68 85/80 pituitary extractWax ester Cholera toxin & Bovine F/M 70/50 67/42 pituitary extractTriglyceride Cholera toxin & Bovine F/M 0 0 pituitary extract

EXAMPLE 11 In vivo Evaluation of the Test Compound Effect on SebumProduction: Human Skin—SCID Mouse Chimera Model

[0172] Severe combined immunodeficient mice (SCID) provide an invaluablemodel for skin xenografting. These animals are devoid of both T and Bcell immunity. Human skin grafts in SCID mice retain human cellulartissue components including skin immune cells, i.e. Langerhans cells,macrophages and lymphocytes and also part of the engrafted endothelium(Kaufman R., et al., Exp. Dermatol. 1993: 2: 209-216, 1993). Theseproperties allow for the study of physiological and/or pathologicalresponses of human skin cells to a test compound.

[0173] Step A: Method of Transplantation:

[0174] C.B-17 scid/scid mice (Taconic, Germantown, N.Y.) were used forgrafting at 5-6 weeks of age. Full thickness human facial skin wasshaved to ˜0.4 mm using a Forman Dermatome. The skin shavings werewashed 3 times in antibiotics and antimycotics (penicillin,streptomycin, fungizone) (Life technologies) in Dulbecco's ModifiedEagle Medium (DMEM, Life Technologies). Eliptical skin˜2.0-2.5×1.0-1.5was grafted onto the prepared graft bed and sutured using 4.0 silk.During surgical procedures the mice were anaesthetized using a mixtureof Ketaset (0.16 mg/g body weight) and Rompun (8.0 μg/g body weight).

[0175] It is well accepted that the wound healing process of thetransplanted skin in the SCID mouse takes one month, at which time thehuman skin can be used for experimental purposes. We also found thatthere is a gradual regeneration of sebaceous glands in the transplantedhuman skin and that these glands are fully regenerated and secrete sebumat 7 weeks as shown by Sebutape and histo-morphometry. Maximum size ofthe glands was observed 3 month post transplantation. The glandsretained their capability to produce human specific sebum and theglandular tissue expressed human specific markers including MC5-R. Sinceglands reached their maximum size at 2-3 month post transplantation theeffects of inhibitors of sebum secretion was tested at this point.

[0176] Step B: Method of Treatment:

[0177] Mice at 2-3 month post transplantation with human facial skinwere used for the studies. The graft area was treated with the testcompound at the desired concentration(s) dissolved in polyethyleneglycol-ethanol (20 μl/2 cm²). Controls were treated with vehicle alone.The test compounds were applied daily, excluding weekends. Sebumsecretion was determined using Sebutape at 15 days and 30 days followingtreatment.

[0178] Step C: Termination of the Experiment:

[0179] The termination of the experiment was determined by preliminaryclinical evaluation of sebum production using SEBUTAPE. At this timehuman skin grafts were excised and representative samples were collectedfor histological evaluation. More particularly, 2 mm punch biopsies wereprepared and used for evaluation of lipid synthesis and total lipidaccumulation in the treated tissues.

[0180] Step D: Evaluation of Lipid Synthesis and Total LipidAccumulation in the Examined Tissues.

[0181] The collected_(—)2 mm punch biopsies were placed individuallyinto 96 well plates in Krebs buffer and labeled with 10 μCi of ¹⁴Cacetate for 3 hours. Following this labeling period the samples werewashed in medium and 5 biopsies pooled, weighed, and used for lipidextraction. The lipid extraction and analysis by HPTLC was the same asdescribed for tissue culture derived cells.

[0182] Following the procedure described above, compound #74 of thepresent invention was tested for the inhibition of sebaceous glandactivity following 11 day treatment of human skin transplanted to theSCID mouse.

[0183] Visual evaluation of the sebaceous gland following topicaltreatment with 0.1% solution of compound #74 resulted in visibleshrinkage of the sebaceous gland and down regulation of sebaceouslipids. Topical treatment for 15 days with 0.05% and 0.005% solutionswas not sufficient to down regulate the lipids. Numerical evaluation ofthe inhibition of human sebaceous lipids for these cells was analyzedusing HPTLC, with results as listed in Table 11, 12 and 13. % Inhibitionnumbers are listed relative to control. TABLE 11 Effect of Compound #74on Human Sebaceous Lipids (11 Day Treatment) Lipid % lnh @ 0.1% % lnh @0.5% % lnh @0.01% Squalene 70 0 0 W/E 80 10 25 Triglycerides 50 0 0

[0184] TABLE 12 Effect of Compound #74 on Lipid Accumulation (30 DayTreatment) Lipid % lnh @ 0.05% % lnh @ 0.01% Squaline 73 82 CholesterolEster 21 44 Wax Esters 93 86 Triglycerides 90 75 Cholesterol 82 33

[0185] TABLE 13 Effect of Compound #74 on Sebaceous Lipid Synthesis (30Day Treatment) Lipid % lnh @ 0.05% % lnh @ 0.01% Squaline 90 80 WaxEsters 93 86 Triglycerides 90 75 Cholesterol 82 33

[0186] As shown in Tables 12 and 13 above, both total sebaceous lipidaccumulation and de novo synthesis of sebaceous lipids was significantlydecreased following 30 days of topical treatment with an 0.05% and 0.01%solution of compound #74.

EXAMPLE 12 Oral Formulation

[0187] As a specific embodiment of an oral composition, 100 mg of thecompound #74 of Example 2 is formulated with sufficient finely dividedlactose to provide a total amount of 580 to 590 mg to fill a size O hardgel capsule.

EXAMPLE 13 Topical Formulations

[0188] A: Microemulsion

[0189] As a specific embodiment of a microemulsion composition thefollowing components are blended, with heating as need: Polysorbate 6020 parts (e.g Tween 60 from ICI Surfactants) Isopropyl Palmitate 20parts Sorbitan Oleate 13 parts (e.g. Span 80 from ICI Surfactants)2-Ethylhexanediol-1,3 4 parts Butylated hydroxy-toluene 0.05 partsCompound #74 0.05 parts

[0190] To the blended mixture is then slowly added water (42.9 parts byweight), with mixing as necessary, to yield the emulsion.

[0191] B: Hydroalcoholic Gel

[0192] As a specific embodiment of a hydroalcoholic gel composition thepolypropylene glycol (10 parts by weight), butylene glycol (10 parts byweight), benzyl alcohol (2 parts by weight), EDTA (0.05 parts by weight)and BHT (0.05 parts by weight) are mixed with water (74.85 parts byweight total). The mixture is blended until all the components aredissolved. Carbomer (e.g. Carbopol 934P from Goodrich) (3 parts byweight) is then slowly added with constant turning to yield a gel.Compound #74 (0.05 parts by weight) is then dispersed into the gel withmixing. The gel pH is adjusted to about pH 3-4.

[0193] C: Anhydrous Gel

[0194] As a specific embodiment of an anhydrous gel isopropanol (20parts by weight) is added to butylene glycol (20 parts by weight). BHT(0.05 parts by weight) and benzyl alcohol (1.0 parts by weight) are thenadded to the isopropanol/butylene glycol mixture. To the resultingmixture is then added Cyclotetrasiloxane (D₄) and Organopolysiloxane-11(e.g. Gransil GSM Gel from Grant Industries) (58.85 parts by weight)with continuous mixing. Compound

What is claimed is:
 1. A compound of the formula (I)

wherein R¹ is selected from the group consisting of aryl, aralkyl,heteroaryl, heteroaryl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl,cycloalkyl and cycloalkyl-alkyl; wherein the aryl, aralkyl, heteroaryl,heterocycloalkyl, heterocycloalkyl-alkyl or cycloalkyl group isoptionally substituted with one or more substituents independentlyselected from halogen, hydroxy, alkyl, alkoxy; halogenated alkyl,halogenated alkoxy, amino, alkylamino or di(alkyl)amino; R² is selectedfrom the group consisting of aryl, aralkyl, heteroaryl, heterocycloalkyland cycloalkyl-alkyl; wherein the aryl, aralkyl, heteroaryl,heterocycloalkyl or cycloalkyl group is optionally substituted with oneor more substituents independently selected from halogen, hydroxy,alkyl, alkoxy; halogenated alkyl, halogenated alkoxy, amino, alkylaminoor di(alkyl)amino; R³ is selected from the group consisting of hydrogen,alkyl, alkenyl and alkynyl; wherein the double bond of the alkenyl orthe triple bond of the alkynyl group is at least one carbon atom removedfrom the point of attachment; R⁴ is selected from the group consistingof aryl, aralkyl, heteroaryl, heterocycloalkyl, and cycloalkyl-alkyl;wherein the aryl, aralkyl, heteroaryl, heterocycloalkyl or cycloalkylgroup is optionally substituted with one or more substituentsindependently selected from halogen, hydroxy, alkyl, alkoxy; halogenatedalkyl, halogenated alkoxy, amino, alkylamino or di(alkyl)amino; X⁻ isselected from the group consisting of bromide, chloride, iodide,acetate, benzoate, citrate, lactate, malate, nitrate, phosphate,diphosphate, succinate, sulfate, tartrate and tosylate; provided thatwhen R¹ is phenyl, chlorophenyl or benzyl, R² is phenyl or benzothienyland R⁴ is phenyl or aralkyl, then R³ is selected from the groupconsisting of alkyl, alkenyl and alkynyl; wherein the double bond of thealkenyl or the triple bond of the alkynyl group is at least one carbonatom removed from the point of attachment; provided further that when R¹is benzyl or methylphenyl, R² is phenyl or methylphenyl and R⁴ ismethylphenyl or 4-methoxyphenyl, then R³ is selected from the groupconsisting of alkyl, alkenyl and alkynyl; wherein the double bond of thealkenyl or the triple bond of the alkynyl group is at least one carbonatom removed from the point of attachment; provided further that when R¹is phenyl, R² is phenyl and R⁴ is phenyl, then R³ is selected from thegroup consisting of C₃₋₈alkyl, alkenyl and alkynyl; wherein the doublebond of the alkenyl or the triple bond of the alkynyl group is at leastone carbon atom removed from the point of attachment; andpharmaceutically acceptable salts thereof.
 2. A compound as in claim 1wherein R¹ is selected from the group consisting of aryl, aralkyl andheteroaryl; wherein the aryl, aralkyl or heteroaryl group is optionallysubstituted with one or more substituents independently selected fromhalogen, hydroxy, alkyl, alkoxy, trihalomethyl, trihalomethoxy, amino,alkylamino or di(alkyl)amino; R² is selected from the group consistingof aryl, aralkyl and heteroaryl; wherein the aryl, aralkyl or heteroarylgroup is optionally substituted with one or more substituentsindependently selected from halogen, hydroxy, alkyl, alkoxy,trihalomethyl, trihalomethoxy, amino, alkylamino or di(alkyl)amino; R³is selected from the group consisting of hydrogen and alkyl; R⁴ isselected from the group consisting of aryl, aralkyl and heteroaryl;wherein the aryl, aralkyl or heteroaryl group is optionally substitutedwith one or more substituents independently selected from halogen,hydroxy, alkyl, alkoxy, trihalomethyl, trihaomethoxy, amino, alkylaminoor di(alkyl)amino; provided that when R¹ is phenyl, chlorophenyl orbenzyl, R² is phenyl or benzothienyl and R⁴ is phenyl or aralkyl, thenR³ is selected from the group consisting of alkyl; provided further thatwhen R¹ is benzyl or methylphenyl, R² is phenyl or methylphenyl and R⁴is methylphenyl or 4-methoxyphenyl, then R³ is selected from the groupconsisting of alkyl; provided further that when R¹ is phenyl, R² isphenyl and R⁴ is phenyl, then R³ is selected from the group consistingof C₃₋₈alkyl; and pharmaceutically acceptable salts thereof.
 3. Acompound as in claim 2 wherein R¹ is aryl; wherein aryl group isoptionally substituted with one to two substituents independentlyselected from halogen, alkyl and alkoxy; R² is aryl; wherein the arylgroup is optionally substituted with one to two substituentsindependently selected from alkyl and alkoxy; R³ is selected from thegroup consisting of hydrogen and alkyl; R⁴ is selected from the groupconsisting of aryl, aralkyl, and heteroaryl; wherein the aryl or aralkylgroup is optionally substituted with one to two substituentsindependently selected from halogen, alkyl and alkoxy; provided thatwhen R¹ is phenyl or chlorophenyl, R² is phenyl and R⁴ is phenyl oraralkyl, then R³ is selected from the group consisting of alkyl;provided further that when R¹ is methylphenyl, R² is phenyl and R⁴ ismethylphenyl or 4-methoxyphenyl, then R³ is selected from the groupconsisting of alkyl; provided further that when R¹ is phenyl, R² isphenyl and R⁴ is phenyl, then R³ is selected from the group consistingof C₃₋₈alkyl; and pharmaceutically acceptable salts thereof.
 4. Acompound as in claim 3 wherein R¹ is selected from the group consistingof phenyl, 2-chlorophenyl, 4-chlorophenyl, 2-methylphenyl,4-methylphenyl, 2-methoxyphenyl and 4-methoxyphenyl, R² is selected fromthe group consisting of phenyl, 4-methylphenyl, 2-methoxyphenyl and4-methoxyphenyl; R³ is selected from the group consisting of hydrogenand methyl; R⁴ is selected from the group consisting of phenyl,2-chlorophenyl, 4-chlorophenyl, 4-bromophenyl, 2-methylphenyl,4-methylphenyl, 2-methoxyphenyl, 4-methoxyphenyl, benzyl,2-chlorobenzyl, 4-chlorobenzyl, 2-methylbenzyl, 4-methylbenzyl,2-methoxybenzyl, 4-methoxybenzyl, 2,6-difluorophenyl,3,5-difluorophenyl, 2-chloro-6-methylphenyl and 3-pridyl; provided thatwhen R¹ is phenyl or chlorophenyl, R² is phenyl and R⁴ is phenyl orbenzyl, then R³ is selected from the group consisting of alkyl; providedfurther that when R¹ is methylphenyl, R² is phenyl and R⁴ ismethylphenyl or 4-methoxyphenyl, then R³ is selected from the groupconsisting of alkyl; provided further that R¹, R² and R⁴ cannot each bephenyl; and pharmaceutically acceptable salts thereof.
 5. A compound asin claim 4, selected from the group consisting of2-(2-methoxyphenyl)-3-(2-methoxyphenyl)-5-phenylamino-[1,2,4]-thiadiazol-2-ium;2-(2-methoxyphenyl)-3-(2-methoxyphenyl)-5-(2-methoxyphenylamino)-[1,2,4]-thiadiazol-2-ium;2-(2-methoxyphenyl)-3-(2-methoxyphenyl)-5-(4-tolylamino)-[1,2,4]-thiadiazol-2ium;2-(2-methoxyphenyl)-3-phenyl-5-(4-methoxyphenylamino)-[1,2,4]-thiadiazol-2-ium;2-(2-methoxyphenyl)-3-phenyl-5-(4-tolylamino)-[1,2,4]-thiadiazol-2-ium;2-(2-methoxyphenyl)-3-phenyl-5-(2-tolylamino)-[1,2,4]-thiadiazol-2-ium;and pharmaceutically acceptable salts thereof.
 6. The compound of claim5 selected from2-(2-methoxyphenyl)-3-(2-methoxyphenyl)-5-phenylamino-[1,2,4]thiadiazol-2-iumor a pharmaceutically acceptable salt thereof.
 7. A pharmaceuticalcomposition comprising a compound as claimed in claim 1 and apharmaceutically acceptable carrier.
 8. A method of making apharmaceutical composition comprising mixing a compound of claim 1 witha pharmaceutically acceptable carrier.
 9. A pharmaceutical compositionmade by mixing a compound of claim 1 and a pharmaceutically acceptablecarrier.
 10. A method of treating a disorder mediated by a melanocortinreceptor comprising administering to a subject in need thereof atherapeutically effective amount of a compound of formula (I)

wherein R¹ is selected from the group consisting of alkyl, aryl,aralkyl, heteroaryl, heteroaryl-alkyl, heterocycloalkyl,heterocycloalkyl-alkyl, cycloalkyl and cycloalkyl-alkyl; wherein thearyl, aralkyl, heteroaryl, heteroaryl-alkyl, heterocycloalkyl,heterocycloalkyl-alkyl, cycloalkyl or cycloalkyl-alkyl group isoptionally substituted with one or more substituents independentlyselected from halogen, hydroxy, alkyl, alkoxy; halogenated alkyl,halogenated alkoxy, amino, alkylamino or di(alkyl)amino; R² is selectedfrom the group consisting of alkyl, aryl, aralkyl, heteroaryl,heterocycloalkyl and cycloalkyl-alkyl; wherein the aryl, aralkyl,heteroaryl, heterocycloalkyl or cycloalkyl-alkyl group is optionallysubstituted with one or more substituents independently selected fromhalogen, hydroxy, alkyl, alkoxy; halogenated alkyl, halogenated alkoxy,amino, alkylamino or di(alkyl)amino; R³ is selected from the groupconsisting of hydrogen, alkyl, alkenyl and alkynyl; wherein the doublebond of the alkenyl or the triple bond of the alkynyl group is at leastone carbon atom removed from the point of attachment; R⁴ is selectedfrom the group consisting of hydrogen, alkyl, aryl, aralkyl, heteroaryl,heterocycloalkyl, and cycloalkyl-alkyl; wherein the aryl, aralkyl,heteroaryl, heterocycloalkyl or cycloalkyl-alkyl group is optionallysubstituted with one or more substituents independently selected fromhalogen, hydroxy, alkyl, alkoxy; halogenated alkyl, halogenated alkoxy,amino, alkylamino or di(alkyl)amino; X⁻ is selected from the groupconsisting of bromide, chloride, iodide, acetate, benzoate, citrate,lactate, malate, nitrate, phosphate, diphosphate, succinate, sulfate,tartrate and tosylate; and pharmaceutically acceptable salts thereof.11. A method as in claim 10 wherein R¹ is selected from the groupconsisting of aryl, aralkyl and heteroaryl; wherein the aryl, aralkyl orheteroaryl group is optionally substituted with one or more substituentsindependently selected from halogen, hydroxy, alkyl, alkoxy,trihalomethyl, trihalomethoxy, amino, alkylamino or di(alkyl)amino; R²is selected from the group consisting of aryl, aralkyl and heteroaryl;wherein the aryl, aralkyl or heteroaryl group is optionally substitutedwith one or more substituents independently selected from halogen,hydroxy, alkyl, alkoxy, trihalomethyl, trihalomethoxy, amino, alkylaminoor di(alkyl)amino; R³ is selected from the group consisting of hydrogenand alkyl; R⁴ is selected from the group consisting of aryl, aralkyl andheteroaryl; wherein the aryl, aralkyl or heteroaryl group is optionallysubstituted with one or more substituents independently selected fromhalogen, hydroxy, alkyl, alkoxy, trihalomethyl, trihaomethoxy, amino,alkylamino or di(alkyl)amino; and pharmaceutically acceptable saltsthereof.
 12. A method as in claim 11 wherein R¹ is aryl; wherein arylgroup is optionally substituted with one to two substituentsindependently selected from halogen, alkyl and alkoxy; R² is aryl;wherein the aryl group is optionally substituted with one to twosubstituents independently selected from alkyl and alkoxy; R³ isselected from the group consisting of hydrogen and alkyl; R⁴ is selectedfrom the group consisting of aryl, aralkyl, and heteroaryl; wherein thearyl or aralkyl group is optionally substituted with one to twosubstituents independently selected from halogen, alkyl and alkoxy; andpharmaceutically acceptable salts thereof.
 13. A method as in claim 12wherein the compound is selected from the group consisting of2-(2-methoxyphenyl)-3-(2-methoxyphenyl)-5-phenylamino-[1,2,4]-thiadiazol-2-ium;2-(2-methoxyphenyl)-3-(2-methoxyphenyl)-5-(2-methoxyphenylamino)-[1,2,4]-thiadiazol-2-ium;2-(2-methoxyphenyl)-3-(2-methoxyphenyl)-5-(4-tolylamino)-[1,2,4]-thiadiazol-2-ium;2-(2-methoxyphenyl)-3-phenyl-5-(4-methoxyphenylamino)-[1,2,4]-thiadiazol-2-ium;2-(2-methoxyphenyl)-3-phenyl-5-(4-tolylamino)-[1,2,4]-thiadiazol-2-ium;2-(2-methoxyphenyl)-3-phenyl-5-(2-tolylamino)-[1,2,4]-thiadiazol-2-ium;and pharmaceutically acceptable salts thereof.
 14. The method of claim10, wherein the disorder mediated by a melanocortin receptor is selectedfrom the group consisting of metabolic disorders, CNS disorders anddermatological disorders.
 15. The method of claim 10, wherein thedisorder mediated by a melanocortin receptor is selected from the groupconsisting of obesity, impaired oral glucoase tolerance, elevated bloodglucose levels, type II diabetes, Syndrome X, diabetic retinopathy,acute neurodegenerative disorders, chronic neurodegenerative disorders,plexopathies, male erectile dysfunction, dry eyes, acne, dry skin, agedskin, seborrheic dermatitis, rosacea, excessive ear wax, meibomian glanddisorder, pseudofolliculitis, yeast infections, dandruff, hiradenitissuppurativa, ocular rosacea and eccrine gland disorder.
 16. The methodof claim 10, wherein the disorder mediated by a melanocortin receptor isselected from the group consisting of obesity, impaired oral glucosetolerance, elevated blood glucose levels, type II diabetes and SyndromeX.
 17. The method of claim 10, wherein the disorder mediated by amelanocortin receptor is selected from the group consisting of acne, dryskin and seborrheic dermatitis.
 18. The method of claim 10, wherein themelanocortin receptor is a selected from the group consisting of themelanocortin-3 receptor, the melanocortin-4 receptor and themelanocortin-5 receptor.